Species Encountered on Foods

7 Metabolites of Various Penicillium Species Encountered on Foods

Mycotoxins and Other Fungal Related Food Problems Downloaded from pubs.acs.org by YORK UNIV on 12/04/18. For personal use only.

A. E. POHLAND and P. MISLIVEC Bureau of Foods, Food and Drug Administration, Washington, D. C. 20204 The number of species in the genus Penicillium which have been shown to produce toxic metabolites is great. A survey of the literature concerning the frequency of occurrence of Penicillium species on foods and feeds has been made, and 13 species have been identified as common contaminants of foods and feeds. The chemistry and toxicological properties of the metabolites produced by these 13 species are discussed. Molds are ubiquitous in nature; in fact it is hard to specify an area or place where a mold will not grow and proliferate. This fact engen dered a tremendous impetus to study molds and the metabolites produced by molds. These studies progressed to the point where one may con fidently say that molds can produce many secondary metabolites—some of which are acutely toxic and some of which have other toxic manifesta tions (i.e., mutagenicity, teratogenicity, or carcinogenicity). However it was not until 1960 (when the problem of aflatoxin, elaborated by the mold Aspergillus flavus, became apparent) that concern arose over these metabolites in foods and feeds. Since that time mold species of many genera besides Aspergillus have been implicated as being capable of producing mycotoxins in foods and feeds; many of these toxins have been identified as the causative agents in various animal illnesses and deaths. Since the number of species in the genus Penicillium known to pro duce toxic metabolites is extensive, it is necessary to exert some caution in assessing the significance of these findings. The studies of the toxins produced by the various Penicillium species over the past decade have implicated the molds in illnesses and deaths of animals. It is therefore essential to evaluate carefully the hazardous potential to humans result ing from exposure to these toxins. To evaluate properly its hazardous potential, one must determine the species of Penicillium that produce mycotoxin in foods and feeds. For 110

7.

POHLAND AND MiSLivEC

of Pénicillium Species

Metabolites

111

e a c h species o n e m u s t c o n s i d e r the f o l l o w i n g p o i n t s : ( a ) h o w f r e q u e n t l y is the species e n c o u n t e r e d a n d o n w h a t f o o d s ; ( b ) w h a t q u a n t i t y of s u c h f o o d is c o n s u m e d b y h u m a n s a n d at w h a t age g r o u p ; ( c ) m e n t a l c o n d i t i o n s are r e q u i r e d b y t h e species m y c o t o x i n s the species

produces;

of a g i v e n species p r o d u c e s

(e)

(g)

which

w h a t p r o p o r t i o n of t h e isolates

the t o x i n ; ( f )

t o x i g e n i c isolate p r o d u c e s ;

what environ

for g r o w t h ; ( d )

h o w m u c h of the t o x i n t h e

h o w t o x i c the t o x i n is i n terms of b o t h

a m o u n t a n d effects; ( h ) does t h e t o x i n o c c u r i n foods a n d feeds, a t w h a t c o n c e n t r a t i o n , a n d is t h e t o x i n stable to f o o d p r o c e s s i n g ; ( i ) are species t h a t o c c u r f r e q u e n t l y b u t w i t h n o h i s t o r y of t o x i g e n i c i t y a c t u a l l y t o x i c ( P . funiculosum

i n field c o r n , for e x a m p l e ) .

T o a n s w e r these questions w e m u s t c o n s i d e r t h e f o l l o w i n g ( a ) t h e t y p e of f o o d w i l l often d e t e r m i n e the m o l d flora, e.g.,

facts:

P.

urticae

is c o m m o n l y f o u n d i n w h e a t flour p r o d u c t s b u t r a r e l y f o u n d i n c o r n o r beans; ( b )

t h e s o u r c e a n d p r o c e s s i n g stage of t h e f o o d also d e t e r m i n e s

t h e flora, e.g.,

a n d P . funiculosum

P. oxalicum

are c o m m o n l y f o u n d

c o r n i n the field w h e r e a s i n storage P . cyclopium predominate; (c)

and P.

on

viridicatum

c o n d i t i o n s of t e m p e r a t u r e a n d m o i s t u r e p r i o r t o a n d

d u r i n g f o o d storage g r e a t l y i n f l u e n c e the m o l d flora; ( d )

detection a n d

i d e n t i f i c a t i o n of t h e m o l d species is n o t a l w a y s s t r a i g h t f o r w a r d . T h i s is p a r t i c u l a r l y t r u e for species of Pénicillium;

m o s t species of Pénicillium

are

difficult to i d e n t i f y a n d are f r e q u e n t l y r e f e r r e d to i n t h e l i t e r a t u r e as a Pénicillium

sp. O t h e r s a r e s l o w g r o w e r s ( e.g., P. islandicum

purogenum)

and P.

pur-

a n d m a y g o u n d e t e c t e d b e c a u s e of t h e o v e r g r o w t h of fast

g r o w i n g species

of Pénicillium

or some o t h e r genus

(e.g.,

Rhizopus).

F r o m o u r o w n studies i t is a p p a r e n t t h a t t h e m a n n e r i n w h i c h t h e m o l d s are i s o l a t e d f r o m t h e f o o d is i m p o r t a n t . F o r e x a m p l e , to d e t e r m i n e t h e m o l d flora of p e p p e r c o r n s , the i s o l a t i o n m e d i u m u s e d w a s agar, a n d m u c h P . islandicum

potato-dextrose

w a s d e t e c t e d ; w i t h d r i e d beans,

however,

m a l t agar w i t h 7 . 5 % N a C l h a d to b e u s e d t o p r e v e n t b e a n g e r m i n a t i o n o n t h e p l a t e , a n d n o P . islandicum

was observed.

I t is p o s s i b l e t h a t t h i s

species w a s n o t a b l e to e s t a b l i s h g r o w t h o n t h e l a t t e r m e d i u m . C o n s i d e r i n g these facts w e p r o p o s e d

t h a t t h e Pénicillium

species

listed i n T a b l e I should be carefully investigated a n d evaluated for their Table I.

Pénicillium

Species Encountered on Foods and Feeds

I P. P.

cyclopium viridicatum

III

II P. P. P. P. P.

oxalicum expansum chrysogenum brevi-compactum funiculosum

P. P. P. P. P. P.

urticae islandicum citrinum variable fréquentons purpurogenum

112

MYCOTOXINS

h a z a r d o u s p o t e n t i a l a r i s i n g f r o m t h e i r o c c u r r e n c e o n foods a n d feeds ( J ) . T h i s list is b a s e d o n the extensive e x p e r i e n c e of m y c o l o g i s t s r e l a t i v e to t h e p r e s e n c e a n d r a t e o f o c c u r r e n c e of these Pénicillium a n d feeds. three

T h e o c c u r r e n c e of Pénicillium

groups:

group

quently encountered,

I—very

species o n f o o d s

species is l i s t e d i n T a b l e I i n

frequently encountered,

and group

III—occasionally

group

II—fre

encountered.

The

m e t a b o l i t e s e l a b o r a t e d b y e a c h of these species w i l l b e d i s c u s s e d l a t e r . S o m e o f the F D A - g e n e r a t e d d a t a c o n c e r n i n g n a t u r a l o c c u r r e n c e o n w h i c h T a b l e I is b a s e d are f o u n d i n T a b l e s I I a n d I I I ( 2 , 3 ) . Table II. Toxicogenic Penicillia Isolated from Commodities D u r i n g F D A Surveys % Commodity

SD

NSD

Species

Dried Beans (114 Samples)

Incidence*

Mycotoxin

0.1 — — 10 of 10 0.4 C i t r i n i n 38 of 51 3.3 P e n i c i l l i c Acid 3 of 15 2.4 C i t r i n i n O o f 15 2.4 O c h r a t o x i n 9 of 9 0.1 P a t u l i n 9 of 9 0.1 G r i s e o fulvin

P. P. P.

brevi-compactum citrinum cyclopium

1.7 3.5 17.3

P. P. P. P.

viridicatum viridicatum urticae urticae

18.0 18.0 0.4 0.4

White Pepper corns (24 Samples)

P. P.

islandicum citrinum

98.0 2.9

2.8 — 23.0 C i t r i n i n

Black Pepper corns (108 Samples)

P. P.

islandicum citrinum

0.1 1.4

0.0 — 0.0 C i t r i n i n

β

No. Isolates Positive

—

10 of 10

—

lof

1

N S D = not surface disinfected; S D = surface disinfected.

S e v e r a l other studies s u p p o r t the i m p o r t a n c e of the species of cillium

l i s t e d i n T a b l e I as i n v a d e r s of foods a n d feeds.

species of Pénicillium P. expansum cyclopium,

Péni-

I n a s t u d y of the

c a p a b l e of r o t t i n g p o m a c e o u s f r u i t s ( i n a d d i t i o n to

w h i c h is n o t o r i o u s i n this r e s p e c t ) M i s l i v e c f o u n d t h a t P. P. funiculosum,

a n d P. purpurogenum

rotters of a p p l e a n d a p p l e p r o d u c t s

w e r e h i g h l y effective

(4).

M i s l i v e c a n d T u i t e ( 5 ) also s t u d i e d d e n t c o r n kernels o b t a i n e d f r o m fields at harvest, f r o m cribs a n d b i n s , a n d f r o m e x p e r i m e n t a l storage tests d u r i n g 1964-1968.

Pénicillium

stored corn (6.4%

o f kernels i n f e c t e d ) , i n c r i b s a m p l e s ( 1 3 . 4 % ) , a n d

species w e r e f o u n d consistently i n u n -

i n c o m m e r c i a l samples of p o o r q u a l i t y . T h e c h i e f species i s o l a t e d f r o m u n s t o r e d kernels w e r e P. oxalicum, P. cyclopium.

P. funiculosum,

a n d to a l i m i t e d extent

T h e c h i e f species i s o l a t e d f r o m s t o r e d kernels w e r e P.

7.

P O H L A N D

A N D

Metabolites

M I S L I V E C


113

Table III. Incidence of Penicillia in 11 Wheat Paste Product Samples No. Samples with Each Species

Species P. Ρ. P. P. P. P. P. P.

cyclopium,

11 2 2 4 1 5 11 5

cyclopium fréquentons funiculosum islandicum luteum purpurogenum urticae viridicatum

P.

brevi-compactum,

of of of of of of of of

11 11 11 11 11 11 11 11

a n d P . viridicatum.

Hesseltine a n d

G r a v e s ( β ) f o u n d i n a n e x h a u s t i v e s t u d y t h a t P. cyclopium, a n d P . citrinum

P.

urticae,

o c c u r r e d most f r e q u e n t l y i n flour a n d r e f r i g e r a t e d d o u g h

products. Finally Ciegler, Mintzlaff, and Leistner (7) of 422 Pénicillium

reported the isolation

strains f r o m 44 m o l d - r i p e n e d sausages c o l l e c t e d i n 11

c o u n t r i e s ; P . viridicatum

a n d P . expansum

w e r e most f r e q u e n t l y e n c o u n

tered. E a r l i e r studies b y L e i s t n e r a n d A y r e s ( 8 ) of m o l d s o c c u r r i n g o n c u r e d meats (sausages a n d h a m s ) s h o w e d Pénicillium 89%

of the sausages a n d o n 8 3 % of t h e h a m s .

o b s e r v e d m o l d s b e l o n g e d to P . expansum, num, P. commune,

and P.

species present o n

T h e most frequently

P. janihinellum,

P.

chrysoge-

viridicatum.

T a b l e I V is a n a t t e m p t to s u m m a r i z e t h e v a r i o u s l i t e r a t u r e reports of o b s e r v e d illnesses a n d deaths of e x p e r i m e n t a l a n i m a l s w h e n e x p o s e d to a substrate m o l d e d w i t h t h e Pénicillium

species l i s t e d i n T a b l e I. A l s o

i n c l u d e d are n a t u r a l o u t b r e a k s of mycotoxicoses.

S e v e r a l r e v i e w articles

also a p p e a r e d i n w h i c h v a r i o u s species of Pénicillium

have been i m p l i

c a t e d i n mycotoxicoses; thus B o r k e r a n d c o - w o r k e r s ( 9 ) c i t e d 2 2 species of Pénicillium

as b e i n g m y c o t o x i g e n i c i n c l u d i n g P . citrinum,

P. islandicum,

P. expansum,

White

P.

a n d P . urticae.

cyclopium, Brook and

( J O ) h a v e l i s t e d 26 species i n c l u d i n g P . brevi-compactum,

chrysogenum, urticae,

P. purpurogenum,

and P.

P. citrinum,

P. cyclopium,

P. islandicum,

P. oxalicum,

P. P.

vindicatum.

O n c e studies s u c h as those o u t l i n e d a b o v e h a v e i d e n t i f i e d m o l d s f r e q u e n t l y f o u n d o n foods a n d feeds, w e c a n d e t e r m i n e w h a t m e t a b o l i t e s a r e p r o d u c e d b y a p a r t i c u l a r species a n d w h e t h e r these m e t a b o l i t e s are toxic. T h e s e questions are p a r t i c u l a r l y r e l e v a n t i f the f o o d or f e e d asso c i a t e d w i t h the f u n g a l species has b e e n i m p l i c a t e d i n a n i m a l illnesses or deaths. W i t h this i n m i n d let us e x a m i n e the k n o w n i n f o r m a t i o n r e l a t i v e to e a c h of the m o l d s l i s t e d i n T a b l e I.

114

MYCOTOXINS

Table I V . Mold P.

cyclopium

corn corn corn c o r n , beans, pickles a a

P.

viridicatum

Subject

Substrate

—

flour,

Pénicillium—

rat mouse sheep cattle mouse

maize barley corn rice rice r i c e , w h e a t , flour, beans, seaweeds

swine, horses pigs, r a t s mice, rats, guinea pigs mice rats mouse

α

α

P.

oxalicum

maize meal corn r i c e , m i s o , beans

ducks, mice, rats mouse mouse

P.

expansum

P.

chrysogenum

culture corn cereal corn cereal miso corn

Japanese q u a i l mouse rabbit mouse rabbit mouse mouse

maize meal malt flour

mouse cattle mouse

flour

mouse

rice rice rice

mouse human chick mouse

P.

brevi-compactum

P.

funiculosum

P.

urticae

filtrate

a

P.

islandicum

P.

citrinum

w h e a t , flour, beans

P.

variable

corn

P.

fréquentons

P.

purpurogenum

β

mouse

corn rice, wheat, grain corn

flour

mouse chicks mouse

Natural outbreaks of mycotoxicoses.

Group

I

I n terms of f r e q u e n c y of o c c u r r e n c e i n foods a n d feeds P . a n d P . vindicatum

cyclopium

a p p e a r to b e m o s t i m p o r t a n t . B o t h of these species

h a v e b e e n studied extensively, a n d they apparently produce

a host

of

s e c o n d a r y m e t a b o l i t e s , s o m e of w h i c h are e x t r e m e l y t o x i c a n d s o m e of

7.

P O H L A N D

A N D

M I S L I V E C

Metabolites


115

Mycotoxicoses Associations Effects (Oral)

Ref.

focal necrosis of m o s t organs, d e a t h l i v e r a n d k i d n e y lesions death death hepatotoxic, nephrotoxic

11,10 12 18 14 26

poisoning c h r o n i c k i d n e y degeneration l i v e r lesions, d e a t h pulmonary tumors h e p a t i c , r e n a l , gastric a n d s c r o t a l lesions neurotoxic, hepatotoxic, nephrotoxic

15 16 17, 18 19 20 26

death reduction i n weight gain, death hepatotoxic, nephrotoxic l i v e r lesions reduction i n weight gain skin reaction death skin reaction nephrotoxic, death reduction i n weight gain death death nephrotoxic hepatotoxic, nephrotoxic hepatoma hepatotoxic, death e d e m a of leg death nephrotoxic reduction i n weight gain, death

21,10 22 26 23 22 24, 10 22 24, 10 26 22 21 25 26 26 27, 28, 29

26 22

reduction i n weight gain, death

22

hepatotoxic, nephrotoxic congestion, h e m o r r h a g e , l i v e r a n d k i d n e y d a m a g e l i v e r lesions

26 SO 22

w h i c h are k n o w n t o e x h i b i t o t h e r t o x i c m a n i f e s t a t i o n s . I n e a c h instance t h e m o l d has b e e n i m p l i c a t e d as t h e c a u s a t i v e o r g a n i s m i n m a n y cases of a n i m a l illness a n d d e a t h (see P . cyclopium.

Table I V ) .

E x t e n s i v e studies of this o r g a n i s m r e s u l t e d i n t h e

i d e n t i f i c a t i o n of a v a r i e t y of m y c o t o x i n s , s o m e of w h i c h h a v e b e e n c o m m o n l y associated w i t h other m o l d species.

F o r example, ochratoxin A

116

MYCOTOXINS

(Structure I ) , a mycotoxin more commonly ochraceus,

associated w i t h

has b e e n f o u n d to b e p r o d u c e d b y P. cyclopium

t o x i n A is a c u t e l y t o x i c ( L D

5 0

=

Aspergillus

(31).

Ochra

2 0 - 2 2 m g / k g , r a t , o r a l ) (32)

a n d has

b e e n i m p l i c a t e d as a p o t e n t teratogen p e n i c i l l i c a c i d ( S t r u c t u r e I I ) (34),

(33).

P. cylopium

a mycotoxin

also p r o d u c e s

( L D o = 12 m g / 2 0 g , 3

m o u s e , o r a l ) ( 3 5 ) t h a t has b e e n i m p l i c a t e d as a possible c a r c i n o g e n a n d t h a t is p r o d u c e d b y at least 12 other species of Pénicillium.

(36)

Later a

series o f e x t r e m e l y toxic t r e m o r g e n i c toxins w e r e i s o l a t e d f r o m P . cyclopium

(37);

these i n c l u d e p e n i t r e m A ( L D

penitrem Β ( L D

5 0

=

5 0

1.05 m g / k g , m o u s e , I P ) ,

= 5.84 m g / k g , m o u s e , I P ) , a n d p e n i t r e m C . T h e s e

m a t e r i a l s w i l l b e d e s c r i b e d i n C h a p t e r 10. Table V . Compound

Formula

Ochratoxin A Penicillic acid Penitrem A (Tremortin A ) Penitrem Β (Tremortin B ) Cyclopiazonic acid Cyclopiazonic acid imine Bissecodehydrocyclopiazonic acid Cyclopiamine Cyclopeptin Dehydrocyclopeptin Cyclopenin Cyclopenol

C20H22N2O3

Viridicatin Viridicatol Palitantin Puberulic acid Puberulonic acid Cyclopolic acid Cyclopaldic acid Isoerythritol Mannitol E m o d i c acid ω-Hydroxyemodin

C H 0 N CuHuOjN Ci H 0 CsKUOe C9H 0 CnHiuOe CnHioOe C Hxo0 CeHuOe CuH80 CisHioOe

C oH 2

1 8

CIN0

C8H10O4 C37H44O6NCI C37H45O5N C20H20N2O3

C20H21N3O2

C26H33N3O5

Ci C Ci C

7

1 7 7

1 7

H H H H

1 6 1 4 1 4 1 4

1 5

4

4

N N 0 0

2 2 3 4

n

2

2 2

4

7

4

4

7

0 0 N N

2 2 2 2

MW 6

404 170 633 583 336 335 338 468 280 278 294 310 237 253 254 198 224 240 238 122 182 300 286

P.

cyclopium M.P.,

°C

169-72 86 237-9d 185-95d 245-6 277-8 168-9

95 202 184 210-11 215d 268 280 164-5 318 298d 147d 224-5 116-20 166-8 363-5 288

7.

POHLAND AND MISLIVEC

CYCLOPIAZONIC ACID IMINE IV

Metabolites


BISSECODEHYDRO CYCLOPIAZONIC ACID V

CYCLOPIAMINE VI

P . cyclopium p r o d u c e s m a n y o t h e r m e t a b o l i t e s (see these a r e a g r o u p o f c o m p l e x

Table V ) ; among

alkaloids: cyclopiazonic acid

I I I ) , cyclopiazonic acid imine (Structure I V ) , zonic acid (Structure V ) , and cyclopiamine

117

(Structure V I ) .

z o n i c a c i d has b e e n s t u d i e d t o x i c o l o g i c a l l y (51)

(Structure

bissecodehydrocyclopiaCyclopia

a n d is a p p a r e n t l y t h e

m a j o r t o x i c c o m p o n e n t i n c e r t a i n P . cyclopium isolates; 2.3 m g A g

(male

rat, I P ) caused convulsions followed b y death suggesting that i t m a y act as a n e u r o t o x i n .

O r a l administration d i d not cause convulsions.

The

m a j o r site of a c t i o n of t h e t o x i n o n o r a l a d m i n i s t r a t i o n a p p e a r e d to b e t h e spleen a n d the k i d n e y ( L D

5 0

— 36 m g / k g , m a l e r a t , o r a l ) .

Metabolites UV, nm

(solvent)

215, 226 295, 227, 225, 224, 225,

333 ( E t O H ) (H 0) 333 ( M e O H ) 286, 297sh ( M e O H ) 253, 384 ( M e O H ) 293 ( M e O H ) 276, 296sh ( M e O H )

293 286 211, 285

(MeOH) (MeOH) 290 (EtOH)

2

230, 320 ( E t O H ) 226, 284, 304sh, 316, 329sh ( M e O H ) 232

245, 278, 322

Ref. 82 88 89 89 Jfi 41 41 42 48 43 44 44 45 45 46 47 47 48 48 49 49 50 50

118

MYCOTOXINS

Ο

Η »H

Η VIRIDICATIN XI

VIRIDICATOL XII

Figure 1.

Ρ

P . cyclopium metabolites

T h e s t r u c t u r a l e l u c i d a t i o n o f these c o m p l e x m a t e r i a l s i s d e s c r i b e d i n a r e v i e w a r t i c l e b y H o l z a p f e l (42) as w e l l as i n m a n y p r e v i o u s p u b l i c a tions b y t h e same a u t h o r ; f o r S t r u c t u r e I I I this i n v o l v e d b a s i c a l l y r e c o g nition a n d combination of t h e indole nucleus a n d t h e tenuazonic systems.

acid

T r e a t m e n t o f c y c l o p i a z o n i c a c i d w i t h 2 5 % aqueous a m m o n i a

g e n e r a t e d S t r u c t u r e I V w h i c h a c c u m u l a t e d d u r i n g later stages o f t h e f e r m e n t a t i o n process.

Structure V is probably a precursor of Structure

I I I since i t a c c u m u l a t e s d u r i n g e a r l y stages o f f e r m e n t a t i o n a n d i s c o n v e r t e d i n t o S t r u c t u r e I I I b y β - c y c l o p i a z o n a t e oxidocyclase t u r e V I a n d its stereoisomer cyclopium

isocyclopiamine

isolate f r o m m o l d y p e a n u t s

( 5 2 ) . Struc

were produced

Another group of interrelated alkaloids produced b y P . is

presumably

m e t h i o n i n e (43)

derived

from

cyclopenol

anthranilic acid,

cyclopium

S-phenylalanine, a n d

(see F i g u r e 1 ) . T h e s e i n c l u d e c y c l o p e p t i n

V I I ) , dehydrocyclopeptin

by a P.

(42).

(Structure

(Structure V I I I ) , cyclopenin (Structure I X ) ,

(Structure X ) , viridicatin

(Structure X I ) , a n d viridicatol

( S t r u c t u r e X I I ) . Structures X I a n d X I I w e r e i s o l a t e d a n d i d e n t i f i e d first. T h u s oxidative degradation of Structure X I readily yields oxalic a c i d and 2-aminobenzophenone,

w h i l e Structure X I I yields

2-amino-3'-hydroxy-

b e n z o p h e n o n e ( 4 5 , 53).

These structures were later confirmed through

t o t a l synthesis (53, 54).

T h e structures of t h e b e n z o d i a z e p i n a l k a l o i d s

( Structures I X a n d X ) w e r e m o r e d i f f i c u l t to o b t a i n ; h o w e v e r , d e g r a d a t i o n studies l e a d i n g t o a n t h r a n i l i c a c i d a n d t h e a p p r o p r i a t e b e n z o i c a c i d , as w e l l as p h y s i c a l d a t a , i n d i c a t e d t h e n a t u r e o f t h e r i n g s y s t e m i n v o l v e d (44).

A t that time i t was k n o w n that treatment w i t h a c i d

converted

Structures I X a n d X t o c a r b o n d i o x i d e , m e t h y l a m i n e , a n d v i r i d i c a t i n a n d

7.

P O H L A N D

viridicatol. (55).

A N D

Metabolites

M I S L I V E C


119

S t r u c t u r e s I X a n d X w e r e l a t e r c o n f i r m e d b y t o t a l synthesis

Furthermore an enzyme

l i u m o f P . viridicatum

(cyclopenase) obtained f r o m the myce

accomplished the same conversion

(57).

o n t h e f o r m u l a o f S t r u c t u r e I X i t w a s r e l a t i v e l y s i m p l e to

Based

formulate

Structures X I a n d X I I . N o studies h a v e b e e n r e p o r t e d r e l a t i v e t o the t o x i c i t y o f a n y of these m e t a b o l i t e s . F i n a l l y P . cyclopium

has b e e n r e p o r t e d to p r o d u c e a n u m b e r of other

metabolites i n c l u d i n g palitantin (Structure X I I I ) , p u b e r u l i c XIV)

(Structure

a n d puberulonic (Structure X V ) acids, cyclopolic (Structure X V I )

and cylopaldic (Structure X V I I ) acids, isoerythritol, m a n n i t o l , a n d a p a i r of a n t h r a q u i n o n e s , e m o d i c a c i d ( S t r u c t u r e X V I I I ) a n d ω-hydroxyemodin (Structure X I X )

(see

Table V ) .

N o t o x i c o l o g i c a l studies h a v e

been

r e p o r t e d f o r a n y o f these m a t e r i a l s . CHO Ο Η Ο , Α ^ Η

CH OH 2

O

H

C

Y ^ V

O

H

H OC^k^cH OCH CYCLOPOLIC ACID 2

s

3

HO^-^Xj^CHa OCH3

EMODIC ACID (R=C0 H) 2

CYCLOPALDIC ACID

-HYDOXYEMODIN (R=CH OH) 2

XVI

P . viridicatum. and

XVIII XIX

XVII

T h i s m o l d is f r e q u e n t l y e n c o u n t e r e d i n s t o r e d grains

o n d e c a y i n g v e g e t a t i o n of t h e s o i l ; i t has b e e n i m p l i c a t e d as t h e

c a u s a t i v e agent i n m a n y instances of a n i m a l illnesses a n d deaths Table I V ) .

T h e s e facts, a l o n g w i t h t h e r e p o r t (19)

of

i n m i c e a t t r i b u t e d to a d m i n i s t r a t i o n of r i c e cultures of P . engendered

extensive r e s e a r c h i n t o the metabolites

(see

carcinogenicity

produced

viridicatum by

this

m o l d . T h e s e studies a p p e a r to i n d i c a t e t h a t t h e r e p o r t e d t o x i c i t y associ a t e d w i t h this m o l d m u s t arise f r o m a v a r i e t y of m y c o t o x i n s , o n l y some of w h i c h have been identified. P . viridicatum

has b e e n o b s e r v e d

to p r o d u c e

m e t a b o l i t e s t h a t are p r o d u c e d b y P . cyclopium (56),

m a n y of the

viridicatin (15), viridicatol (57), cyclopenin and cyclopenol

cyclopolic

a n d c y c l o p a l d i c a c i d (48),

same

including ochratoxin

mannitol, and isoerythritol

A

(45), (see

T a b l e V ) . I n a d d i t i o n r e c e n t findings s h o w t h a t o c h r a t o x i n Β ( S t r u c t u r e

120

MYCOTOXINS

'3

CH

4-HYDROXYOCHRATOXIN A XX

3

CH

3

CITRININ •XXII

XXI

I ) , 4-hydroxyochratoxin A (Structure X X ) , a n d 7-carboxy-3,4-dihydro-8hydroxy-3-methyl isocoumarin vindicatum

(Structure X X I ) are elaborated

by P.

( 5 8 ) . T h e s e structures w e r e e l u c i d a t e d b y c a r e f u l l y e v a l u

a t i n g s p e c t r a l d a t a ; t o x i c o l o g i c a l studies i n d i c a t e t h a t these d e r i v a t i v e s o f o c h r a t o x i n A are r e l a t i v e l y n o n t o x i c ( 3 2 ) . K r o g h a n d co-workers

(16, 17) i n t h e i r studies o f f u n g a l n e p h r o

toxicity isolated a n d identified oxalic a c i d a n d citrinin (Structure X X I I ) f r o m corn-steep l i q u o r cultures o f P . viridicatum. o r i g i n a l l y f r o m P . citrinum

C i t r i n i n was isolated

cultures ( 5 9 ) . F r i i s , H a s s e l a g e r , a n d K r o g h

( 16) o b s e r v e d t h a t f e e d i n g S t r u c t u r e X X I I t o s w i n e r e s u l t e d i n a n e p h r o p a t h y s i m i l a r to t h e n a t u r a l l y o c c u r r i n g p o r c i n e n e p h r o p a t h y ; also c i t r i n i n w a s a c u t e l y toxic t o m i c e ( L D

5 0

= 3 5 m g / k g , S C ) (60).

M u c h effort

w a s e x p e n d e d t o assign t h e s t r u c t u r e o f c i t r i n i n ; i t w a s k n o w n ( 5 9 ) t h a t d i l u t e a c i d c o n v e r t e d c i t r i n i n i n t o t w o p h e n o l s (Αχ, o p t i c a l l y a c t i v e a n d B i , o p t i c a l l y i n a c t i v e ) t h a t w h e n f u s e d w i t h a base y i e l d e d a m a t e r i a l w i t h the empirical formula C H i 0 . 9

as 4 - m e t h y l - 5 - e t h y l - r e s o r c i n o l

2

2

T h i s m a t e r i a l w a s later i d e n t i f i e d

( F i g u r e 2 ) (61).

Beconverting the opti

cally actively phenol ( C i i H i 0 ) t o citrinin then established t h e structure 6

for citrinin

3

(61,62).

M y c o p h e n o l i c a c i d ( S t r u c t u r e X X I I I ) has also b e e n i s o l a t e d f r o m P . viridicatum compactum

(64).

T h i s m a t e r i a l w a s o r i g i n a l l y i s o l a t e d f r o m P . brevi-

a n d is often r e f e r r e d t o as t h e first a n t i b i o t i c substance i s o

lated a n d purified from molds

(LD

5 0

= 2500 m g / k g , m o u s e , o r a l ) .

OH

Figure 2.

The structure of citrinin

A

7.

POHLAND A N D MISLIVEC

MYCOPHENOLIC ACID XXIII

Metabolites

121


VIRIDICATIC ACID XXIV

TERRESTRIC ACID XXV

good review b y B . J . W i l s o n covering the structural identification a n d b i o l o g i c a l a c t i v i t y o f this m a t e r i a l has b e e n p u b l i s h e d (65). to m y c o p h e n o l i c tetronic

acids

a c i d c u l t u r e filtrates o f P . viridicatum viridicatic acid

(Structure

XXIV)

I n addition

also p r o d u c e t h e a n d terrestric

acid

(Structure X X V ) ; from the mycelium mannitol, isoerythritol, a n d ergos t e r y l p a l m i t a t e w e r e o b t a i n e d (66).

Structure X X I V was determined b y

r e l a t i n g its p h y s i c a l properties t o those o f c a r l o s i c a c i d w h i c h has a b u t y r y l g r o u p i n t h e «-position, a n d b y h y d r o l y s i s to n-hexanoic

a c i d a n d β-

hydroxylaevulic acid. T w o f u r t h e r metabolites o f P . viridicatum

have been isolated a n d

identified: brevianamide A (Structure X X V I ) ( 6 7 ) , a compound origi n a l l y i s o l a t e d f r o m P . brevi-compactum ture X X V I I )

( 6 8 ) , and xanthomegnin

( 6 9 ) , a c o m p o u n d originally isolated from

(A.B)

XANTHOMEGNIN XXVII

XXVI magnini

N e i t h e r o f these m a t e r i a l s appears

(70).

toxic to m i c e .

(Struc

Trichophyton

appreciably

orally

F i n a l l y a r e p o r t (71) r e c e n t l y a p p e a r e d d e s c r i b i n g a n e w

m y c o t o x i n , v i r i d i c u m t o x i n (C30H31NO10) ( L D

5 0

— 122.4 m g / k g , rat, oral),

T h e m o l d s i n this g r o u p a r e e n c o u n t e r e d

f r e q u e n t l y o n foods a n d

of u n k n o w n structure ( T a b l e V I ) . Group

II

feeds ( T a b l e I ) a n d h a v e t h e p o t e n t i a l to p r o d u c e t o x i n ( T a b l e I V ) . H o w e v e r these m o l d s h a v e n o t y i e l d e d t h e l a r g e n u m b e r s o f toxins n o t e d f o r G r o u p I m o l d s , n o r h a v e t h e y b e e n s t u d i e d as extensively ( w i t h t h e possible exception of P . P . oxalicum. from this m o l d .

chrysogenum).

V e r y f e w metabolites h a v e b e e n i s o l a t e d a n d i d e n t i f i e d I t p r o d u c e s o x a l i c a c i d (71) w h i c h a p p a r e n t l y i s t o x i c

122

MYCOTOXINS

Table V I . Compound

Formula

Ochratoxin Β 4-Hydroxyochratoxin A 7-Carboxy-3,4-dihy dro8-hydroxy-3-methyl isocoumarin Oxalic acid Citrinin Mycophenolic acid Viridicatic acid Terrestric acid Brevianamide A Xanthomegnin Viridicumtoxin

C oH N0 C oH CIN0 2

1 9

2

1 8

6

7

C11H10O5

C2H2O4 C13H14O5

Pénicillium

MW

M.P.,

369 419 222

220-1 216-8 223

90 250 320 256 211 365 574 565

101 175d 141 174.5 89 215-230 285-300d 211

o n l y i n e x t r e m e l y h i g h dosage. B e c e n t l y , h o w e v e r , P . oxalicum b e e n s h o w n to p r o d u c e s e c a l o n i c a c i d D

°C

has also

(Structure X X V I I I ) and two

n e w a l k a l o i d s of u n k n o w n s t r u c t u r e , one of w h i c h w a s c a l l e d o x a l i n e T a b l e V I I ) . T h e structure of secalonic a c i d D w a s d e t e r m i n e d

(see

spectro-

s c o p i c a l l y b y r e l a t i n g its p r o p e r t i e s to those of its o p t i c a l a n t i p o d e ( s e c a l o n i c a c i d A ) , one of the toxic p i g m e n t s e l a b o r a t e d b y Claviceps P. expansum. this m o l d species. patulin (73)

purpurea.

A g a i n l i t t l e is k n o w n of t h e m e t a b o l i t e s p r o d u c e d

by

T h e m a j o r t o x i n i s o l a t e d a n d i d e n t i f i e d appears to b e

( S t r u c t u r e X X I X ) w h i c h is m o r e c o m m o n l y associated w i t h

the m o l d P . urticae

(see

d i s c u s s i o n of P . urticae).

T h e fact that P.

expan

sum is t h e m a j o r c o n t r i b u t o r to a p p l e r o t has e n g e n d e r e d m u c h interest i n t h e p o s s i b l e o c c u r r e n c e of p a t u l i n i n a p p l e p r o d u c t s .

P . expansum

is

also k n o w n to p r o d u c e c u r v u l a r i n ( S t r u c t u r e X X X ) , a m a t e r i a l c l o s e l y r e l a t e d to the estrogenic m a t e r i a l z e a r a l e n o n e P. chrysogenum.

(106).

T h i s m o l d has b e e n e x t e n s i v e l y s t u d i e d f r o m the have not

been

r e p o r t e d for this species a l t h o u g h a w i d e d i v e r s i t y o f m e t a b o l i t e s

s t a n d p o i n t of p e n i c i l l i n p r o d u c t i o n .

have

ο SECALONIC XXVIII

OH ACID D

T o x i c metabolites

PATULIN ΧΧΙΧ

CURVULARIN ΧΧΧ

7.

P O H L A N D

A N D

123


Metabolites

M I S L I V E C

Metabolites

viridicatum

UV, nm (solvent)

Ref.

218, 318 ( E t O H ) 213, 334 ( E t O H ) 218, 322 ( E t O H )

58 58 58

16, 17 63 64 66 66 67 69 71

222, 253, 319 ( E t O H ) 230, 268 ( E t O H ) 234, 256sh, 405 ( M e O H ) 227, 290sh, 395 ( C H C 1 ) 237, 285, 317, 331, 347, 424 ( E t O H ) 3

b e e n r e p o r t e d (see

Table V I I ) .

These include penicillin F

(Structure

X X X I ) , d e t h i o b i o t i n ( S t r u c t u r e X X X I I ) , adenosine-5-phosphate, 5-phosphate,

adenylosuccinic acid, chrysogine

inosine-

(Structure X X X I I I ) , and

tetracosanoic a c i d . B a l l i o a n d c o - w o r k e r s d e t e c t e d at least 16 d e r i v a t i v e s of adenosine, guanosine, i n o s i n e , c y t i d i n e , a n d u r i d i n e i n the m y c e l i u m of P . chrysogenum

(77).

I n a d d i t i o n S u t e r a n d T u r n e r (82)

PENICILLIN F XXXI

DETHIOBIOTIN χχχ,Ι

reported

CHRYSOGINE ΧΧΧΙΙΙ

the p r e s e n c e of 2 - p y r u v o y l a m i n o b e n z a m i d e ( S t r u c t u r e X X X I V ; not s h o w n ) i n t h e c u l t u r e filtrate of P . chrysogenum. w i t h a n y of these

N o t o x i c i t y has b e e n associated

compounds.

P . brevi-compactum.

T h i s m o l d is of p a r t i c u l a r interest since i t w a s

i n v o l v e d i n one of t h e earliest attempts ( 1 8 9 6 ) to relate a t o x i n p r o d u c e d b y a m o l d to the i n c i d e n c e of a h u m a n i l l n e s s — p e l l a g r a i n this case (83).

A l t h o u g h n o r e l a t i o n s h i p c o u l d b e e s t a b l i s h e d , w o r k i n this a r e a

d i d r e s u l t i n the first c h e m i c a l d e t e c t i o n system d e v i s e d to d e t e c t s p o i l a g e of m a i z e b a s e d o n the c o l o r r e a c t i o n b e t w e e n f e r r i c c h l o r i d e a n d p h e n o l i c metabolites. series

of

Raistrick a n d co-workers

phenolic

i s o l a t e d a n d i d e n t i f i e d (83)

materials i n c l u d i n g mycophenolic

acid

a

(Structure

X X I I I ) ( T a b l e V I ) , 3,5-dihydroxy-2-carboxybenzyl m e t h y l ketone (Struc ture X X X V ) , XXXVI) ,

3,5-dihydroxy-2-carboxyphenylacetyl

3,5-dihydroxy-2-carboxylbenzoyl

methyl

carbinol

(Structure

ketone

(Structure

X X X V I I ) , a n d 3,5-dihydroxyphthaUc a c i d (Structure X X X V I I I ) .

Later

124

MYCOTOXINS

xxxv

χχχνι

XXXVII

w o r k e r s i n v e s t i g a t i n g t h e biosynthesis o f m y c o p h e n o l i c a c i d i s o l a t e d t w o additional

metabolites:

5,7-dihydroxy-4-methylphthaUde

( Structure

X X X I X ) and6-famesyl-5,7-d%droxy-4-methylphthalide ( S t r u c t u r e X L ) . F i n a l l y s e v e r a l other m y c o p h e n o l i c

a c i d derivatives (Structures X L I -

X L I I I ) have been reported (Table V I I I ) .

I n a t t e m p t i n g t o isolate t h e h e p a t o t o x i c P . brevi-compactum

B i r c h a n d co-workers

substances

produced

by

i s o l a t e d a series o f n e u t r a l

compounds, mostly pigments: brevianamides A - F ( T a b l e V I I I ) . Struc t u r e X X V I ( b r e v i a n a m i d e A ) w a s d e t e r m i n e d first, b a s e d o n a c o m b i n a t i o n o f p h y s i c a l m e t h o d s w i t h b i o g e n e t i c hypotheses.

Brevianamide Β

w a s q u i c k l y s h o w n to b e a stereoisomer o f S t r u c t u r e X X V I . I r r a d i a t i o n of Structure X X V I ( A a n d Β ) yields brevianamides C (Structure X L I V ) a n d D ( S t r u c t u r e X L V ) w h i c h are s i m p l y c i s - t r a n s isomers; r e d u c t i o n o f these isomers w i t h N a B H

4

y i e l d s a single i n d o l e ( S t r u c t u r e X L V I ) . Table V I I .

Compound Oxalic acid Secalonic acid D Oxaline Patulin Curvularin Penicillin F Dethiobiotin Adenosine-5'-phosphate Inosine-5'-phosphate Adenylosuccinic acid C h o l i n e sulfate Chrysogine Tetracosanoic acid 2-Pyruvoylaminobenzamide

C2H2O4 C32H30O14 C24H25N5O4

C H2o0 N CioHi803N Ci H O N C H O N C H 0nN C5H 0 N 4

1 4

2

0

1 4

7

6

1 3

8

4

1 4

1 8

1 3

4

S

2

1 0

y

MW

Formula

C7H6O4 C16H20O5

M e t a b o l i t e s o f P . oxalicum

P P P

6

6

C10H10O2N2 C24H48O2 C10H10N2O3

M.P.,

°C

90 638

101 253-254

154 292 312 214 347 347 468 183 190 369 206

111 206-7 204d 156-8 178 191-5d

189-90 87.5 181H1

7.


Metabolites


B r e v i a n a m i d e Ε a n d F w e r e assigned Structures X L V I I

and

125

XLVIII

based on physical data. T h e biogenetic precursor Structure X L I X postu lated b y B i r c h (91).

(90)

has r e c e n t l y b e e n i s o l a t e d f r o m Aspergillus

ustus

D e t a i l s of the biosynthesis of t h e b r e v i a n a m i d e s as w e l l as t h e i r

t o x i c o l o g i c a l effects a r e u n d e r s t u d y .

XLVI

P. expansum,

and P.

XLVII

chrysogenum

UV, nm (solvent) 248, 337 ( E t O H ) 277 ( M e O H ) 223, 271.5, 304 ( E t O H )

226, 230, 238, 265, 273, 292, 305, 316 ( E t O H ) 2 1 1 , 247, 302 ( M e O H )

Ref. 71 72 72 78 74 75 76 77 77 78 79 80 81 83

126

MYCOTOXINS

P. funiculosum.

M e t a b o l i t e s p r o d u c e d b y this m o l d species i n c l u d e

malonic acid, orsellinic acid (Structure L ) , a n uncharacterized

antiviral

agent, h e l e n i n e , w h i c h is t h o u g h t to b e a n u c l e o p r o t e i n , a n d t h e a n t h r a q u i n o n e f u n i c u l o s i n w h i c h is i d e n t i c a l to i s l a n d i c i n ( S t r u c t u r e L I ) (see

ORSELLINIC ACID L

ISLANDICIN LI

Table VIII. Compound 3,5-Dihydroxy-2-carboxyb e n z y l - m e t h y l ketone 3,5-Dihydroxy-2-carboxyphenyl-acetyl carbinol 3,5-Dihydroxy-2-carboxyb e n z o y l m e t h y l ketone 3,5-Dihydroxyphthalic acid 6-Farnesyl-5,7-dihydroxy4-methylphthalide E t h y l mycophenate Structure X L I I Mycochromenic acid Brevianamide A Β C D Ε F Isoerythritol Dihydroxyacetone M a l o n i c acid Orsellinic acid Funiculosin Mitorubrin Mitorubrinol Mitorubrinic acid Funicone

Formula

MW

Metabolites of M.P.,

°C

C10H10O5

210

152-6d

CioHioOe

226

200d

C10H10O7

224

125-35

CsHeOe

198 384

188 (206) 98-100

348 336 318 365 365 365 365 367 283 122 90 104 168 270 382 398 412 374

88-90 218-20 163-165 190-220 324-8d Glass Glass Glass 173-5 116-20 75-80 135 176 218 218 219-21

C24H32O4 C19H24O6 C17H20O7

CnHisOe C21H23N3O3 C21H23N3O3 C21H23N3O3 C21H23N3O3

C21H25N3O3

C H N 02 1 6

1 7

3

C4H10O4

CjHeOs C3H4O4

CeH80

4

C15H10O5 C21H18O7

CîiHieOe C^lHieOg CigHigOe

176-8

7.

P O H L A N D

A N D

Table V I I I ) .

M I S L I V E C

Metabolites


I n a d d i t i o n a series of metabolites

have been

127

isolated

w h i c h a r e s t r u c t u r a l l y s i m i l a r to t h e s c l e r o t i o r i n ( a z a p h i l o n e ) g r o u p of metabolites

(93);

these i n c l u d e m i t o r u b r i n ( S t r u c t u r e L I I ) , a c o m p o u n d

o r i g i n a l l y i s o l a t e d f r o m P . rubrum,

mitorubrinol (Structure L U I ) , mito-

r u b r i n i c a c i d ( S t r u c t u r e L I V ) , a n d f u n i c o n e ( S t r u c t u r e L V ) (see VIII).

P. brevi-compactum UV,

and P.

nm (solvent)

funiculosum Ref. 83

88 84 85, 86 303 245, 235, 236, 234, 235, 239, 277,

280, 256, 254, 259, 264, 296 283,

321.5, 332.5 404 ( M e O H ) 400 ( E t O H ) 450 ( E t O H ) 306, 470 ( E t O H ) (EtOH) 292 ( E t O H )

216, 266, 292, 346 ( E t O H ) 216, 266, 292, 346 ( E t O H ) 245, 310 ( 9 5 % E t O H )

87 87 87 88 89 89 89 89 89 49 92 94 95 96 97 97 98 98

Table

Group

HI

M o l d s i n this g r o u p are o n l y o c c a s i o n a l l y f o u n d o n foods a n d feeds. H o w e v e r , t h e y a r e i m p o r t a n t w i t h respect to c e r t a i n types of foods a n d d o p r o d u c e s o m e v e r y t o x i c , a n d i n some cases carcinogenic, metabolites. P . urticae

( P . patulum).

T h i s m o l d species has b e e n i m p l i c a t e d as

the causative agent i n a n outbreak of fatal poisoning of dairy cows i n Japan ( 9 9 ) . It was concluded that the toxin involved was patulin (Struc ture X X I V ) .

P a t u l i n is p r o d u c e d i n h i g h y i e l d s b y P . urticae

tremely toxic ( L D

5 0

=

i m p l i c a t e d as a c a r c i n o g e n (36).

Its c h e m i s t r y a n d toxicology h a v e b e e n

reviewed b y Ciegler, Detroy, and Lillehoj P . patulum

a n d is ex

0.7 m g / 2 0 g, mouse, o r a l ) ; p a t u l i n has also b e e n (106).

also p r o d u c e s t h e e x t r e m e l y u s e f u l a n t i m i c r o b i a l agent

g r i s e o f u l v i n ( S t r u c t u r e L V I ) . I t is s t i l l p r e s c r i b e d as a systemic t h e r a p e u t i c agent f o r cutaneous f u n g a l infections, a l t h o u g h i t a p p a r e n t l y has some carcinogenic

properties

T h e chemical a n d toxicological

(107).

properties of griseofulvin are carefully reviewed i n B . J . Wilson's article Table I X . Formula

Compound Griseofulvin Dehydrogriseofulvin 2,6-Dihydroxy-4-methyl8-methoxyxanthone 4,6-Dimethoxy-2'-methylg r i s a n - 3 , 4 ' ,6'-trione Structure L X Structure L X I Gentisic acid Gentisaldehyde G e n t i s y l alcohol 6-Methysalicylic acid 6-Formylsalicylic acid 3-Hydroxyphthalic acid Pyrogallol p-Hydroxybenzoic acid Anthranilic acid Gentisylquinone

MW

Metabolites of M.P.,

°C

C15H12O5

353 351 272

220 270-275 253-5

CieHieOe

304

245-8d

C17H17O5CI

337 353 154 138 140 152 166 182 126 138 137 138

181-2 212-4 199

C17H17O6CI

CnHiôOeCl

CnHnOeCl C7H6O4 C7IÏ6O3 C7H8O3

CeHeC^ CeHeOô CeHeOs C7H6O3

C H 0 N 7

7

2

C7H6O3

100 170 134 154 134 213 144 76

7.

P O H L A N D

A N D

Metabolites

M I S L I V E C

of Pénicillium Species OCH3

ο

129

ο

ΌΗ

CH^>,

Ο CH 0 3

•H

O

CH

3

LIX

LVIII

ΌΗ

R

o n miscellaneous Pénicillium

LX

R=OCH.

LXI

R=CH,

toxins ( 1 0 8 ) . I n a d d i t i o n , P . patulum

d u c e s five a d d i t i o n a l m a t e r i a l s r e l a t e d to d e h y d r o g r i s e o f u l v i n LVII),

2,6-dihydroxy-4-methyl-8-methoxyxanthone

4,6-dimethoxy-2 -methylgrisan-3,4 ,6 -trione ,

,

/

pro

(Structure

(Structure

LVIII),

(Structure L I X ) , and a pair

of s u s b t i t u t e d b e n z o p h e n o n e s ( S t r u c t u r e s L X a n d L X I ) ( T a b l e I X ) . t o x i c o l o g i c a l properties F i n a l l y P . patulum

of these m a t e r i a l s a r e a p p a r e n t l y n o t

p r o d u c e s m a n y p h e n o l i c c o m p o u n d s (see

w h i c h a p p a r e n t l y a r e i n t e r r e l a t e d b i o s y n t h e t i c a l l y (see

The

known.

Table I X )

Figure 3)

(104).

N o t o x i c i t y has b e e n associated w i t h these m a t e r i a l s . P . islandicum.

F e w molds have been studied more extensively or

s y s t e m a t i c a l l y t h a n P . islandicum. P. urticae

(P.

Interest i n t h e m e t a b o l i t e s of P .

patulum)

UV, nm (solvent) 236, 252, 241, 324 ( M e O H ) 242, 289, 330 ( E t O H ) 242, 269, 309, 340 ( E t O H )

Ref. 100 109 109 109

296 ( E t O H ) 298 ( E t O H )

323

109 109 101 101 102 103 104 104 104 104 104 105

islandi-

130

MYCOTOXINS

Figure 3. cum

Metabolites

of P. patulum

arises m a i n l y from e a r l y findings that r i c e n a t u r a l l y m o l d e d b y P . ( y e l l o w e d r i c e ) c o u l d cause acute a n d c h r o n i c l i v e r d a m a g e

islandicum

w h e n f e d t o m i c e (110).

T h i s finding c o u p l e d w i t h t h e f a c t t h a t A s i a t i c

p o p u l a t i o n s i n w h i c h r i c e forms a m a j o r p o r t i o n o f t h e d i e t also suffer f r o m a h i g h i n c i d e n c e o f l i v e r diseases i n c l u d i n g p r i m a r y h e p a t i c c a r c i n o m a (99) produced

gave i m p e t u s to a great d e a l o f r e s e a r c h i n t o t h e m e t a b o l i t e s b y P . islandicum

a n d their toxicological properties.

studies l e d e v e n t u a l l y to t h e i s o l a t i o n o f t w o e x t r e m e l y p o t e n t toxins, l u t e o s k y r i n ( L D

These hepato-

= 2.21 m g / k g , mouse, o r a l ) a n d c y c l o c h l o r o -

5 0

t i n e ( L D o = 6.55 m g / k g , m o u s e , 5

o r a l ) , b o t h o f w h i c h are b e l i e v e d

c a r c i n o g e n i c ( 2 3 ) . I n a d d i t i o n a s e c o n d e x t r e m e l y toxic p e p t i d e , i s l a n d i t o x i n ( m i n i m u m l e t h a l dose 3.6 m g / k g , S C , m o u s e ) h a s b e e n i s o l a t e d a n d i d e n t i f i e d (111, 112).

A n excellent r e v i e w o f these m a t e r i a l s as w e l l

as other toxins r e l a t e d to y e l l o w e d r i c e h a s a p p e a r e d P. ishndicum

(113).

p r o d u c e s a t least 2 7 q u i n o i d a l p i g m e n t s (see T a b l e X )

w h i c h m a y b e c o n v e n i e n t l y a r r a n g e d i n three groups.

T h e first g r o u p

Monomeric Anthraquinones

HO Chrysophanol Islandicin Emodin Catenarin ω-Hydroxyemodin Endocrocin

R, = H R = H R = C H , R, = H Η CH, Η OH OH Η Η CHs OH CH» Η OH Η OH Η CH OH C0 H OH Η CH, 2

Ο

OH

Ο

OH

8

2

2

TETRAHYDROCATENARIN LXIII

7.


Metabolites

131


contains the m o n o m e r i c a n t h r a q u i n o n e s , a l l of w h i c h are d e r i v a t i v e s o f c h r y s o p h a n o l ( S t r u c t u r e L X I I ) : i s l a n d i c i n , e m o d i n , c a t e n a r i n , ω-hydroxyemodin, endocrocin, tetrahydrocatenarin ( Structure L X I I I ) , and dihydrocatenarin.

The

structures

of

these

quinones

are r e a d i l y d e r i v e d

c o m p a r i n g t h e i r p h y s i c a l p r o p e r t i e s , i n c l u d i n g c o l o r tests

by

(magnesium

a c e t a t e ) , u v , i r , N M R s p e c t r a , a n d x - r a y d i f f r a c t i o n d a t a , w i t h those of e q u i v a l e n t m a t e r i a l s o b t a i n e d t h r o u g h t o t a l synthesis.

These

synthetic

procedures generally involve the F r i e d e l - C r a f t s condensation of a p h t h a l i c anhydride w i t h a suitable phenol.

R e c e n t l y K e n d e et a l . (119)

reported

a n e w a p p r o a c h t o t h e t o t a l synthesis of i s l a n d i c i n i n v o l v i n g regiospecific p h o t o - F r i e s r e a r r a n g e m e n t (see

F i g u r e 4).

Dimeric Anthraquinones

OH

Dianhydrorugulosin Iridoskyrin Skyrin Dicatenarin Oxyskyrin Skyrinol Roseoskyrin Auroskyrin Rhodoislandin A Rhodoislandin Β Punicoskyrin Aurantioskyrin

Ο

Ri= R = H R, = H , R - O H R, = O H , R = h R, = R = O H One methyl of skyrin = C H O H Both methyls of skyrin = C H O H (chrysophanol + islandicin) (chrysophanol -j- emodin) (chrysophanol + catenarin) (emodin + islandicin) (catenarin -j- islandicin) (catenarin + emodin) 2

2

2

2

2

2

T h e s e c o n d g r o u p contains the d i m e r i c a n t h r a q u i n o n e s LXV):

(Structure

dianhydrorugulosin, iridoskyrin, skyrin, dicatenarin, oxyskyrin,

skyrinol, roseoskyrin, auroskyrin, rhodoislandin A , rhodoislandin B , p u n i c o s k y r i n , a n d a u r a n t i o s k y r i n ( T a b l e X ) . T h e structures of these m a t e r i a l s were

established p r i m a r i l y through reductive

Figure 4.

cleavage

Total synthesis of islandicin

with

alkaline

132

MYCOTOXINS

Table X . Compound

MW

Formula

Chrysophanol Islandicin Emodin Catenarin ω-Hydroxyemodin (citreorosein) Endocrocin (clavoxanthin) Tetrahydrocatenarin Dihydrocatenarin (+) Dianhydrorugulosin (+) Iridoskyrin (+) Skyrin (+) Dicatenarin (+) Oxyskyrin (+) Skyrinol ( + ) Roseoskyrin (+) Auroskyrin (+) Rhodoislandin A (+) Rhodoislandin Β (+) Punicoskyrin (+) Aurantioskyrin ( —) L u t e o s k y r i n ( —) R u b r o s k y r i n ( —) F l a v o s k y r i n ( —) R u g u l o s i n ( — ) Deoxyluteoskyrin ( —) D e o x y r u b r o s k y r i n ( —) 4 - a - O x y l u t e o s k y r i n Erythroskyrine Islanditoxin Cyclochlorotine 3-Hydroxyphthalic acid M a l o n i c acid s o d i u m d i t h i o n i t e (114)

Metabolites M.P.,

°C

C15H10O5 C15H10O5 C15H10O6 C15H10O6

254 270 270 286 286

195-6 218 256-7 244-6 288

C16H10O7

314

290-320d

290 288 538 538 538 570 554 570 522 522 538 538 554 554 574 574 544 542 558 558 590 455 572 605 182 104

~130d 95-105d 321 358-60d >360d >300d >360d >360 275-380d >300 >300 >300 >300 >300 281d 289d 215d 290d 293 255 >250d 130-3 258 251d 166 135

C15H10O4

C15H14O6 C15H12O6

C30H18O10 C30H18O10 C30H18O10 C30H18O12

CeoHisOn C30H18O12 C30H18O9 C30H18O9 C30H18O10 C30H18O10 C30H18O11 C30H18O11 C30H22O12 C30H22O12 C30H24O10

C30H22O10 C30H22O11 C30H22O11 C30H22O13 C26H33O6N C25H3608N5C12

CsHeOô C3H404

to t h e c o r r e s p o n d i n g m o n o m e r i c q u i n o n e s a n d

t h r o u g h i n s p e c t i o n o f t h e N M R s p e c t r a of t h e acetates (120).

Thus, for

example, reductive cleavage of dianhydrorugulosin yields two molecules of c h r y s o p h a n o l (see

F i g u r e 5). N o t e t h a t a l l of these m a t e r i a l s e x h i b i t oh

"S* '2

OH

"IL*

0

DIANHYDRORUGULOSIN

Figure 5.

0

Reduction of dimeric

CHRYSOPHANOL

anthraquinones

7.


Metabolites


islandicum

of P.

UV,

Ref.

nm (solvent)

228, 257, 277, 287, 429 ( E t O H ) 231.5, 252, 288, 490, 512 ( E t O H ) 253, 266, 289, 436 ( E t O H ) 231, 257, 282, 492, 525 ( E t O H ) 221, 252, 290, 438, 458 s h ( E t O H )

114 115 116 116 117

274, 442 ( M e O H )

118

485, 514, 554 ( E t O H ) 495 (530i, 570i) ( E t O H ) 282 s h , 439 ( D i o x i n ) 286, 502 ( D i o x i n ) 257, 300, 462 ( E t O H )

117 117 128 121 114 1 &\J 122 120 120 120 120 120 120 120 m m 125 m m m 124 126 112 127 128 129

257, 300, 462 ( E t O H ) 258, 290, 448 ( D i o x a n )

280, 275, 267, 253,

133

350, 440 ( E t O H ) 4 1 5 , 435, 530, 540 (CHC1») 303, 312, 328, 368, 414 ( D i o x a n e ) 396.5 ( C H C 1 ) 3

280, 369, 380, 510, 531, 570 ( D i o x a n e ) 392, 409 ( E t O H ) 253, 259, 265 ( M e O H )

optical activity attributable to restricted rotation a r o u n d the b o n d

con

n e c t i n g t h e t w o m o n o m e r i c h a l v e s . C u r r e n t l y n o i n f o r m a t i o n is a v a i l a b l e c o n c e r n i n g t h e t o x i c i t y of these d i a n t h r a q u i n o n e s . T h e t h i r d g r o u p contains the m o d i f i e d b i a n t h r a q u i n o n e s ( T a b l e luteoskyrin (Structure L X V I , R = O H ) , R=OH),

flavoskyrin

X):

mbroskyrin (Structure

LXVII,

(Structure L X V I I I ) , rugulosin (Structure

LXIX),

deoxyluteoskyrin (Structure L X V I , R = H ) ,

deoxyrubroskyrin

(Structure

L X V I I , R = H ) , a n d 4 - a - o x y l u t e o s k y r i n ( S t r u c t u r e L X X ) . T h e structures of these c o m p o u n d s w e r e v e r y difficult to d e t e r m i n e ; t h e y w e r e r e s o l v e d b y c a r e f u l i n t e r p r e t a t i o n of t h e N M R s p e c t r a a n d w e r e firmed,

finally con

at least for r u g u l o s i n , b y x - r a y d i f f r a c t i o n studies ( 1 2 3 ) . F i g u r e 6

M Y C O T O X I N S

FLAVOSKYRIN LXVIII

Figure 6.

4-K-OXYLUTEOSKYRIN LXX

Modified bianthraquinones

from P . islandicum

7.

POHLAND

AND

Metabolites

MISLIVEC


135

ci

CI

ISLANDITOXIN LXXII

OH CH(CH ) CH 2

I II II / NH-C-CHNH-C-T

*

"\

5

3

}

Η

ο R U B R A T O X I N A (R=H, R'=0H)

:YCLOCHLOROT LXXIII

=0)

Β (R,R=

shows some of the o b s e r v e d i n t e r r e l a t i o n s h i p s b e t w e e n these m a t e r i a l s . P. islandicum

also p r o d u c e s the e x t r e m e l y t o x i c ( L D

5 0

=

60 m g / k g ,

mouse, i p ) metabolite erythroskyrine (Structure L X X I ) (113,126).

The

s t r u c t u r e of this p i g m e n t w a s d e t e r m i n e d b y c h e m i c a l d e g r a d a t i o n ex p e r i m e n t s w h i c h i n d i c a t e d the presence of t h e p o l y e n e system

(—CH=

C H — ) , the t e n u a z o n i c a c i d m o i e t y , a n d the d i a n h y d r o s o r b i t o l structure. 5

T h e r o l e of this c o m p o u n d i n i n t o x i c a t i o n b y P . islandicum-iniested

rice

has n o t y e t b e e n d e t e r m i n e d . F i n a l l y P . islandicum

p r o d u c e s t w o w a t e r - s o l u b l e , hexatotoxic, c y c l i c

peptides—islanditoxin (Structure L X X I I ) a n d cyclochlorotine LXXIII)

(see

Table X ) .

T h e tentative structures of these

(Structure extremely

t o x i c m a t e r i a l s h a v e b e e n d e d u c e d b y h y d r o l y s i s experiments

(112,127);

h o w e v e r some of the investigators i n this field f e e l t h a t these t w o toxins m a y be identical P.

variable.

(129). L i t t l e is k n o w n of the m e t a b o l i t e s p r o d u c e d b y this

m o l d . H o w e v e r i t p r o d u c e s ( + ) - r u g u l o s i n ( S t r u c t u r e L X I X ) , ergosterol, and

its p e r o x i d e

(130). T h i s m o l d is f r e q u e n t l y f o u n d o n foods

P. purpurogenum.

and

feeds a n d has b e e n i m p l i c a t e d i n m a n y cases of a n i m a l illnesses a n d deaths ( T a b l e I V ) .

I t has r e c e n t l y b e e n s h o w n (131)

c a p a b l e of p r o

d u c i n g h i g h y i e l d s of the e x t r e m e l y t o x i c m a t e r i a l s r u b r a t o x i n s A a n d Β (Structure L X X I V ) toxins h a v e b e e n

(LD

5 0

—100-200

commonly

m g / k g , oral, rat).

associated w i t h P . rubrum;

r e v i e w of the subject b y M . O . M o s s has b e e n p u b l i s h e d

These an (132).

myco

excellent

136

MYCOTOXINS

Ο Ο C H ^

LXXV LXXVI

PURPURIDE

PURPUROGENONE R=OH DEOXYPUPUROGENONE R=H

P . purpurogenum

LXXVI I

also p r o d u c e s c o p i o u s a m o u n t s

o f some h i g h l y

c o l o r e d p i g m e n t s ; a f e w o f these h a v e b e e n i s o l a t e d a n d i d e n t i f i e d . include

purpurogenone

(Structure L X X V I ,

(Structure

LXXV)

and

These

deoxypurpurogenone

T a b l e X I ) . T h e structure of purpurogenone

was

d e t e r m i n e d b y x - r a y c r y s t a l l o g r a p h i c analysis of t h e m o n o b r o m o a c e t a t e (145).

I t has b e e n s u g g e s t e d t h a t t h e p i g m e n t i s b i o s y n t h e s i z e d

t w o m o l e c u l e s o f e m o d i n via a n u n d e f i n e d s e q u e n c e o f reactions T h e s t r u c t u r e a s s i g n e d to d e o x y p u r p u r o g e n o n e

from (134).

was based on a compari

son o f its s p e c t r a l d a t a w i t h those o b t a i n e d f r o m p u r p u r o g e n o n e ,

the

f o r m a t i o n o f a pentaacetate i n s t e a d o f a hexaacetate a n d o x i d a t i v e d e g r a dation to 3-hydroxy-5-methylphthalic anthraquinone

(135).

acid and l,4-dihydroxy-2-methyl-

I n a d d i t i o n to Structures L X X V

and L X X V I

a

t h i r d , colorless m a t e r i a l w a s i s o l a t e d a n d g i v e n t h e t r i v i a l n a m e p u r p u r i d e ( S t r u c t u r e L X X V I I ) w h i c h w a s d e t e r m i n e d b y d i r e c t x - r a y analysis. T h e t o x i c o l o g i c a l p r o p e r t i e s of these c o m p o u n d s h a v e n o t b e e n i n v e s t i g a t e d . Table X I . Compound Purpurogenone Deoxypurpurogenone Purpuride Glauconic acid Glaucanic acid A n t i b i o t i c S L 3238 D - M a n n o n i c acid Alloisocitric acid Citromycetin Frequentin Sulochrin Asterric acid ( + ) Bisdechlorogeodin Questin Questinol Hadacidin Rubratoxin A Rubratoxin Β Mannitol

Formula

Metabolites Produced b y MW

M . P . , °C

7.

P O H L A N D

A N D

M I S L I V E C

Metabolites


137

GLAUCONIC ACID R=OH LXXVIII GLAUCANIC ACID R=H LXXIX

P . purpurogenum

also p r o d u c e s

a pair of nonadrides,

glauconic

( S t r u c t u r e L X X V I I I ) a n d g l a u c a n i c ( S t r u c t u r e L X X I X ) a c i d s , so n a m e d because they are constructed f r o m t w o identical C fragments. L i k e the 9

r u b r a t o x i n s these acids c o n t a i n t h e r e l a t i v e l y stable b i s a n h y d r i d e s t r u c t u r e . T h e structures o f these c o m p o u n d s w e r e e s t a b l i s h e d p r i m a r i l y b y degradation experiments c o u p l e d w i t h x-ray crystallographic data

{146).

T h e k e y p y r o l y t i c d e g r a d a t i o n p r o d u c t , g l a u c o n i n , w a s i d e n t i f i e d as a C o p e r e a r r a n g e m e n t p r o d u c t , a n d its s t r u c t u r e w a s p r o v e d b y synthesis (see F i g u r e 7 ) . F i n a l l y a n a n t i b i o t i c ( S L 3238-C27H41NO2) o f u n k n o w n s t r u c t u r e is r e p o r t e d to b e p r o d u c e d b y P . purpurogenum

(see T a b l e X I ) .

N o t o x i c o l o g i c a l i n f o r m a t i o n is a v a i l a b l e a b o u t t h i s m a t e r i a l . P . frequentans.

A s its n a m e i m p l i e s , this m o l d is c o m m o n l y f o u n d

i n a l l types o f m a t e r i a l s . N o n e o f t h e c o m m o n l y k n o w n m y c o t o x i n s , h o w ever, h a v e b e e n i s o l a t e d f r o m t h i s m o l d a l t h o u g h s e v e r a l metabolites a r e k n o w n (see T a b l e X I ) . T h e s e i n c l u d e c i t r o m y c e t i n ( S t r u c t u r e L X X X ) , P . purpurogenum

and P .

frequentans

UV, nm (solvent)

Ref.

253, 308, 388, 499, 530, 570 ( C H C 1 , ) 251, 275, 309, 389, 490, 529 ( C H C 1 ) 216.5 ( E t O H ) 223 220 3

232, 290 ( D i o x a n e ) 250, 215, 224, 224,

317 ( E t O H ) 285 ( E t O H ) 248, 285, 4 2 5 ( E t O H ) 247, 286, 4 3 2 ( E t O H )

250 ( C H C N ) 250 ( C H C N ) 3

3

m 185 136 137 187 188 189 H0 m 142 143 148 143 143 143 144 183 133 181

138

MYCOTOXINS

R RCH=è-CHO GLAUCONIN

Figure

7.

Formation

of ghuconin acid

from

glauconic

OH k - ^ V ^ V ^ ^ O H FREQUENTIN

/ V V ^ ^ O H J

4

"

k / V ^ \ ^ ^

PALITANTOL

LXXXI

Figure 8.

OR

H

PALITANTIN XIII

Rehtionship

between frequentin

OH

OH

SULOCHRIN

ASTERRIC ACID LXXXI II

LXXXII

and palitantin

O ^ BISDECHLOROGEODIN LXXXIV

QUESTIN R=CH LXXXV QUESTINOL R =CH OH LXXXVI 3

7

2

f r e q u e n t i n ( S t r u c t u r e L X X X I ; F i g u r e 8), p a l i t a n t i n ( S t r u c t u r e X I I I ; see P . cyclopium),

sulochrin (Structure L X X X I I ) , asterric a c i d

L X X X I I I ) , bisdechlorogeodin

(Structure

(Structure L X X X I V ) , a n d a p a i r of a n -

thraquinone pigments, questin (Structure L X X X V ) a n d questinol (Struc ture L X X X V I ) .

T h e structure of citromycetin was based p r i m a r i l y o n

7.


Metabolites


139

d e g r a d a t i o n results i n w h i c h m e t h y l - O - d i m e t h y l c i t r o m y c e t i n w a s w i t h permanganate

to y i e l d

cleaved

2-carboxy-3-hydroxy-5,6-dimethoxybenzoate

( 1 3 7 ) . F r e q u e n t i n ( S t r u c t u r e L X X X I ) w a s q u i c k l y d e d u c e d b y its r e a d y conversion

into palitantol, a product

(Structure X I I I ) b y N a B H produces

sulochrin

4

readily obtained

reduction (Figure 8).

(Structure

L X X X I I I ) , and bisdechlorogeodin

LXXXII),

asterric

palitantin

acid

also

(Structure

(Structure L X X X I V ) ; the latter t w o

c o m p o u n d s are i n t e r r e l a t e d i n t h a t b i s d e c h l o r o g e o d i n i n t o asterric a c i d s i m p l y b y h e a t i n g i n w a t e r . b e e n p r e v i o u s l y i s o l a t e d f r o m Oospora ture of b i s d e c h l o r o g e o d i n

from

P . frequentans

is e a s i l y c o n v e r t e d

A l l three c o m p o u n d s h a d

sulphurea-ochracea,

a n d the struc

has b e e n c o n f i r m e d b y t o t a l synthesis

T h e structures of q u e s t i n ( S t r u c t u r e L X X X V )

and questinol

(143).

(Structure

L X X X V I ) w e r e established t h r o u g h degradation experiments a n d c o m p a r i s o n w i t h d e r i v a t i v e s of e m o d i n a n d ω-hydroxyemodin.

N o toxicity

has b e e n associated w i t h a n y of these m a t e r i a l s .

Conclusion T h e 13 Pénicillium

species i d e n t i f i e d as c o m m o n l y

f o u n d o n foods

p r o d u c e a l a r g e n u m b e r of m e t a b o l i t e s ; s o m e of these m a y b e classified as t r u e m y c o t o x i n s .

H o w e v e r , l i t t l e is k n o w n a b o u t t h e t o x i c o l o g i c a l p r o p

erties of m a n y of t h e m e t a b o l i t e s , a n d this needs to b e s t u d i e d .

Finally

v e r y l i t t l e is k n o w n a b o u t t h e o c c u r r e n c e of these m e t a b o l i t e s i n foods a n d feeds.

Literature

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Cited

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140

MYCOTOXINS

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7.


Metabolites

of Penicillium Species

141

56. van Walbeek, W., Scott, P. M., Harwig, J., Lawrence, J. W., Can. J. Microbiol. (1969) 15, 1281. 57. Luckner, M., Mohammed, Y. S., Tetrahedron Lett. (1964) 29, 1987. 58. Hutchison, R. D., Steyn, P. S., Thompson, D. L., Tetrahedron Lett. (1971) 43, 4033. 59. Hetherington, A. C., Raistrick, H., Trans. Roy. Soc. (London) (1931) Β 220, 269. 60. Cartwright, N . J., Robertson, Α., Whalley, W. B., Nature (1949) 163, 94. 61. Brown, J. P., Cartwright, N . J., Robertson, Α., Whalley, W. B., Nature (1948) 162, 72. 62. Johnson, D. H., Robertson, Α., Whalley, W. B., J. Chem. Soc. (1950) 2971. 63. Cartwright, N . J., Robertson, Α., Whalley, W. B., J. Chem. Soc. (1949) 1563. 64. Burton, H. S., Brit. J. Exp. Pathol. (1949) 30, 151. 65. Wilson, B. J., in "Microbial Toxins," Vol. VI, A. Ciegler, S. Kadis, S. J. Ajl, Eds., p. 459, Academic, New York, 1971. 66. Birkinshaw, J. H., Samant, M. S., Biochem. J. (1960) 74, 369. 67. Wilson, B. J., Yang, D. T., Harris, T. M., Appl. Microbiol. (1973) 26 (4), 633. 68. Birch, A. J., Wright, J. J., Chem. Commun. (1969) 644. 69. Pohland, A. E., Stack, M. E., unpublished data. 70. Just, C., Day, W., Blank, F., Can. J. Chem. (1963) 41, 74. 71. Hutchinson, R. D., Steyn, P. S., van Rensburg, S. J., Toxicol. Appl. Pharmacol. (1973) 24, 507. 72. Steyn, P. S., Tetrahedron (1970) 26, 51. 73. Scott, P. M., Miles, W. F., Taft, P., Dube, J. G., J. Agric. Food Chem. (1972) 20 (2), 450. 74. Birch, A. J., Musgrave, O. C., Richards, R. W., Smith, H., J. Chem. Soc. (1959) 3146. 75. Clarke, H . J., Johnson, J., Robinson, R., "The Chemistry of Penicillin," Princeton University, Princeton, 1949. 76. Tatum, E. L., J. Biol. Chem. (1945) 160, 455. 77. Ballio, Α., Casinovi, C., Serlupi-Crescenzi, G., Biochim. Biophys. Acta (1956) 20, 414. 78. Ballio, Α., Serlupi-Crescenzi, G., Nature (1957) 179, 154. 79. deFlines, J., J. Amer. Chem. Soc. (1955) 77, 1676. 80. Hikino, H., Nabetani, S., Takemoto, T., J. Pharm. Soc. Jap. (1973) 93 (5), 619. 81. Peck, R. L., Anderson, R. J., J. Biol. Chem. (1941) 140, 89. 82. Suter, P. J., Turner, W. B., J. Chem. Soc. (1967) 2240. 83. Clutterbuck, P. W., Oxford, A. E., Raistrick, H., Smith, G., Biochem. J. (1932) 26, 1441. 84. Oxford, A. E., Raistrick, H., Biochem. J. (1932) 26, 1902. 85. Canonica, L., Kroszcynski, W., Ranzi, B. M., Rindone, B., Scolastico, C., Chem. Commun. (1971) 257. 86. Ibid. (1970) 1357. 87. Campbell, I. M., Calzadilla, C. H., McCorkindale, N . J., Tetrahedron Lett. (1966) 42, 5107. 88. Birch, A. J., Wright, J. J., Tetrahedron (1970) 26, 2329. 89. Birch, A. J., Russel, R. Α., Tetrahedron (1972) 28, 2999. 90. Birch, A. J., J. Agric. Food Chem. (1971) 19 (6), 1088. 91. Steyn, P. S., Tetrahedron (1973) 29, 107. 92. Godin, P., Biochim. Biophys. Acta (1953) 11, 114. 93. Whalley, W. B., Pure Appl. Chem. (1963) 7, 565. 94. Yamamoto, T., J. Pharm. Sci. Jap. (1955) 75, 761. 95. Mosbach, Κ., Z. Naturforsch. (1959) 14b, 69.

142

MYCOTOXINS

96. Igarasi, H., J. Agric. Chem. Soc. Jap. (1939) 15, 225. 97. Buchi, G., White, J. D., Wogan, G. N., J. Amer. Chem. Soc. (1965) 87 (15), 3484. 98. Merlini, L., Nasini, G., Selva, Α., Tetrahedron (1970) 26, 2739. 99. Uraguchi, K., Tatsuno, T., Tsukioka, M., Sakai, Y., Sakai, F., Koboyashi, Y., Saito, M., Enomoto, M., Miyaki, M., Jap. J. Exp. Med. (1961) 31, 1. 100. Grove, J. F., MacMillan, J. T., Mulholland, T. P. C., Rogers, M. A. T., J. Chem. Soc. (1952) 3949. 101. Birkinshaw, J. H., Bracken, Α., Michael, S. Α., Raistrick, H . , Lancet (1943) 245, 625. 102. Birkinshaw, J. H., Bracken, Α., Raistrick, H., Biochem. J. (1943) 37, 726. 103. Anslow, W. K., Raistrick, H., Biochem. J. (1931) 25, 39. 104. Bassett, E. W., Tanenbaum, S. W., Experientia (1958) 14, 38. 105. Engel, B. G., Brzesk, W., Helv. Chim. Acta (1947) 30, 1472. 106. Ciegler, Α., Detroy, R. W., Lillehoj, Ε. B., in "Microbial Toxins," Vol. VI, A. Ciegler, S. Kadis, S. J. Ajl, Eds., p. 409, Academic, New York, 1971. 107. Paget, G. E., Walpole, A. L., Nature (1958) 182, 1320. 108. Wilson, B. J., in "Microbial Toxins," Vol. VI, A. Ciegler, S. Kadis, S. J. Ajl, Eds., Academic, New York, 1971. 109. McMaster, W. J., Scott, A. I., Trippett, S., J. Chem. Soc. (1960) 4628. 110. Miyake, M., Saito, M., Enomoto, M., Shikata, T., Ishiko, T., Uraguchi, K., Sakai, F., Tatsuno, T., Tsukioka, M., Sakai, Y., Sato, T., Acta Pathol. Jap. (1960) 10, 75. 111. Marumo, S., Sumiki, Y., J. Agric. Chem. Soc. (1955) 29, 305. 112. Marumo, S., Bull. Agric. Chem. Soc. Jap. (1959) 23 (5), 428. 113. Saito, M., Enomoto, M., Tatsuno, T., in "Microbial Toxins," Vol. VI, A. Ciegler, S. Kadis, S. J. Ajl, Eds., p. 299, Academic, New York, 1971. 114. Howard, Β. H., Raistrick, H., Biochem. J. (1954) 56, 56. 115. Howard, Β. H., Raistrick, H., Biochem. J. (1949) 44, 227. 116. Gatenbeck, S., Acta Chem. Scand. (1958) 12, 1985. 117. BuLock, J. D., Smith, J. R., J. Chem. Soc. (1968) 1941. 118. Gatenbeck, S., Acta Chem. Scand. (1959) 13 (2), 386. 119. Kende, A. S., Belletire, J. L., Hume, E. L., Tetrahedron Lett. (1973) 31, 2935. 120. Ogihara, Y., Kobayashi, N., Shibata, S., Tetrahedron Lett. (1968) 15, 1881. 121. Howard, Β. H., Raistrick, Α., Biochem. J. (1954) 57, 212. 122. Shibata, S., Takido, M., Ohta, Α., Kurosu, T., Chem. Pharm. Bull. (1957) 6, 573. 123. Kobayashi, N., Iitaka, Y., Sankawa, U., Ogihera, Y., Shibata, S., Tetrahedron Lett. (1968) 58, 6135. 124. Takeda, N . , Seo, S., Ogihara, Y., Sankawa, U., Iitaka, I., Kitagawa, I., Tetrahedron Lett. (1973) 29, 3703. 125. Seo, S., Sankawa, U., Ogihara, Y., Iitaka, Y., Shibata, S., Tetrahedron (1973) 29, 3721. 126. Shojii, J., Shibata, S., Chem. Ind. (1964) 419. 127. Ishikawa, I., Ueno, Y., Tsunoda, H.,I..Biochem. (1970) 67 (6), 753. 128. Gatenbeck, S., Acta Chem. Scand. (1957) 11 (3), 555. 129. Shibata, S., private communication. 130. Yamazaki, M., Fujimoto, H., Miyaki, K., Yakugaku Zasshi (1972) 92 (1), 101. 131. Natori, S., Sakaki, S., Kurata, H., Udagawa, S., Ichinoe, M., Saito, M., Umeda, M., Ohtsubo, K., Appl. Microbiol. (1970) 19 (4), 613. 132. Moss, M. O., in "Microbial Toxins," Vol. VI, A. Ciegler, S. Kadis, S. J. Ajl, Eds., p. 381, Academic, New York, 1971. 133. Buchi, G., Snader, Κ. M., White, J. D., Gougoutas, J. Z., Singh, S.,J.Amer. Chem. Soc. (1970) 92, 6638.

7.

134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146.

POHLAND

AND

MISLIVEC

Metabolites


143

Roberts, J. C., Thompson, D. J., J. Chem. Soc. (1971) 3488. Roberts, J. D., Thompson, D. J., J. Chem. Soc. (1971) 3493. King, T. J., Roberts, J. C., Thompson, D. J., J. Chem. Soc. (1973) 78. Barton, D. H. R., Sutherland, J. K., J. Chem. Soc. (1965) 1769. Bollinger, P., Sigg, H. P., Haerri, E., Ger. Patent 2,005,976 (1970) ; Chem. Abstr. (1970) 73, 108. Angeletti, Α., Cerruti, C. F., Ann. Chim. Appl. (1930) 20, 424. Beppu, T., Abe, S., Sakaguchi, R., Bull. Agric. Chem. Soc. (1957) 21, 263. Cavill, G. W., Robertson, Α., Whalley, W. B., J. Chem. Soc. (1950) 1031. Sigg, H . P., Helv. Chim. Acta (1963) 46, 1061. Mahmoodian, Α., Stickings, C. E., Biochem. J. (1964) 92, 369-378. Kaczka, Ε. Α., Citterman, C. O., Dulaney, E. L., Folkers, K., Biochem. J. (1962) 1, 340-43. King, T. J., Roberts, J. C., Thompson, D. J., Chem. Commun. (1970) 1499. Baldwin, J. E., Barton, D. H . R., Bloomer, J. L., Jackman, L. M., Rodriguez-Hahn, L., Sutherland, J. K., Experientia (1962) 18, 345.

RECEIVED November 8, 1974.

Species Encountered on Foods

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