Mycotoxins and Other Fungal Related Food Problems

14 Helminthosporium, Drechslera, and Bipolaris Toxins Downloaded by KTH ROYAL INST OF TECHNOLOGY on June 7, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch014

ODETTE L. SHOTWELL and J. J. ELLIS Northern Regional Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Ill. 61604 Metabolites produced by Helminthosporium and Drechslera (Bipolaris) species include: pigments—polyhydroxyanthraquinones and polyhydroxyxanthones; antibiotics—ophiobolins, monocerins, siccanin, and helmintin; mycotoxin— sterigmatocystin; phytotoxin—helminthosporal; pathotoxins from Drechslera carbonum, D. victoriae, D. maydis, and D. sacchari, and teratogenic compounds—cytochalasins. Most of these compounds are toxic either to animals or plants. Others such as the polyhydroxyanthraquinones and polyhydroxyxanthones belong to classes of compounds known to be toxic. With the exception of the pathotoxins there is little evidence for the natural occurrence of Helmin thosporium and Drechslera toxins. The mycotoxin sterigmatocystin has been found in moldy grain collected on a farm in Canada.

Many

biologically active compounds are produced by species of Helminthosporium Link and Drechslera Ito ( Bipolaris Shoem. ). Toxins include the pigments described by Raistrick and co-workers in a series of papers beginning in 1933. Almost all the pigments, polyhydroxyanthra quinones and polyhydroxyxanthones, came from molds implicated in plant diseases. Much later Helminthosporium and Drechslera species were found to produce antibiotics, but these were too toxic for human therapy. Although the pathotoxins have been studied extensively, the structure of only one has been elaborated—helminthosporiside. Helmin thosporal, one of the better known Helminthosporium phytotoxins, dam ages cereal crops. Sterigmatocystin, a carcinogen whose metabolic path way is related to that an aflatoxin B , is formed by an unidentified species of the genus. The cytochalasins form one of the more important groups 1

318 Rodricks; Mycotoxins and Other Fungal Related Food Problems Advances in Chemistry; American Chemical Society: Washington, DC, 1976.

14.

SHOTWELL

319

Helminthosporium

A N D ELLIS

of m e t a b o l i t e s b e c a u s e of t h e i r t e r a t o g e n i c p r o p e r t i e s a n d are c o n s i d e r e d to b e m y c o t o x i n s .

Cytochalasins are p r o d u c e d b y A s p e r g i l l i ,

a n d p r o b a b l y Phomopsis

Phoma,

as w e l l as b y

Helminthosporium

Species i n this g r o u p of m o l d s i n c l u d e the g e n e r a

Helminthosporium

Zygosporium, species. a n d Drechslera

T h e s e x u a l stages of the g r o u p a r e

(Bipolaris).

bolus R i e s s , Trichometasphaeria

M u n k , Cochliobolus

F r . , a n d Leptosphaeria

phora

C e s . et

de N o t .

Downloaded by KTH ROYAL INST OF TECHNOLOGY on June 7, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch014

y o u m u s t l o o k u n d e r a l l these names.

Pyreno-

W h e n examining the

l i t e r a t u r e f o r s e c o n d a r y m e t a b o l i t e s a n d toxins p r o d u c e d b y sporium

Ophio-

Drechsler,

Helmintho-

T h e r e are reviews that

c o v e r m u c h of the e a r l i e r w o r k o n these p h y t o t o x i n s , p a t h o t o x i n s , a n d s e c o n d a r y m e t a b o l i t e s (1,2,3,4).

W o r k since t h e n w i l l b e e m p h a s i z e d

here. P a t h o t o x i n s are p h y t o t o x i n s p r o d u c e d b y p l a n t disease f u n g i t h a t a r e host specific (3).

T h a t is, a p a t h o t o x i n causes a l l the s y m p t o m s of

a g i v e n disease e v e n i f its p r o d u c i n g f u n g u s is n o t present.

Resistance

o r s u s c e p t i b i l i t y i n a g i v e n p l a n t strain a p p l i e s to b o t h t h e f u n g u s a n d the p a t h o t o x i n i t forms.

O f the seven k n o w n host-specific toxins, f o u r

are p r o d u c e d b y Helminthosporium

species:

M u r p h y ) S u b r a m . et J a i n , H. carbonum d i a l state of Cochliobolus

carbonus

D r e c h s l e r ] , a n d H.

sacchari

( B u t l e r ) S u b r a m . et J a i n ]

victoriae

N e l s o n ) , H. maydis

c o n i d i a l state of Cochliobolus

[Drechslera

D.

Butler

(Meehan

U l l s t r u p ( t h e Drechslera

et

coni-

N i s i k et M i y a k e

heterostrophus

(Drechsler)

[ s y n o n y m of Drechslera

sacchari

(2).

T h e best k n o w n p a t h o t o x i n , v i c t o r i n f o r m e d b y D . victoriae,

is t h e

c a u s a t i v e agent f o r leaf b l i g h t of the V i c t o r i a v a r i e t y of oats ( 5 ) .

I t has

b e e n i s o l a t e d a n d p a r t i a l l y c h a r a c t e r i z e d . T h e t o x i n is a p o l y p e p t i d e complex that can be broken d o w n b y m i l d alkali treatment into two components: a pentapeptide a n d a basic tricyclic compound, victoxinine ( 5 ) . H y d r o l y s i s of the p e n t a p e p t i d e y i e l d s the c o m m o n a m i n o a c i d s — aspartic, glutamic, valine, glycine, a n d leucine. nontoxic.

T h e pentapeptide

V i c t o x i n i n e is t o x i c to oats, r y e , b a r l e y , w h e a t , a n d

is

grain

s o r g h u m l a c k i n g t h e s e l e c t i v i t y or host s p e c i f i c i t y of the c o m p l e t e t o x i n ( 6 ) . E v i d e n t l y t h e specificity of the c o m p l e t e t o x i n is a f u n c t i o n of the pentapeptide moiety.

Victorin

( a c t i v e at 0.01 f t g / m l ) is a b o u t

7500

times as t o x i c as v i c t o x i n i n e o n a w e i g h t basis to s u s c e p t i b l e oat species. A l t h o u g h v i c t o x i n i n e has b e e n c h a r a c t e r i z e d , the s t r u c t u r e of t h e p e n t a p e p t i d e a n d t h e n a t u r e of its a t t a c h m e n t to v i c t o x i n i n e i n t h e p a t h o g e n r e m a i n s to b e d e t e r m i n e d . T h e m e c h a n i s m of the a c t i o n of v i c t o r i n i n p l a n t s d e p e n d s o n the c o m p l e t e s t r u c t u r e . S o p h i s t i c a t e d t e c h n i q u e s exist t h a t s h o u l d m a k e the e l u c i d a t i o n of the c o m p l e t e s t r u c t u r e p o s s i b l e . F o r s t r u c t u r a l studies v i c t o x i n i n e C 1 7 H 2 9 N O w a s i s o l a t e d f r o m c u l ture

filtrates

of H.

sativum

Pammel, King

et

Bakke

[the

Rodricks; Mycotoxins and Other Fungal Related Food Problems Advances in Chemistry; American Chemical Society: Washington, DC, 1976.

Drechslera

320

MYCOTOXINS


I.

Victoxinine

IV.

R = Η

V.

R = MeS02

Figure

I.

c o n i d i a l state of Cochliobolus

II.

R = Η,ΟΗ

III.

R = 0

Victoxinine and compounds sativus

et D a s t u r ] i n 8 - 1 2 m g q u a n t i t i e s ( 7 ) . spectrum,

a n d biogenetic

Prehelminthosporol

(Ito

related

et K u r i b a y a s h i ) D r e c h s l e r

T h e acetylated derivative, N M R

r e l a t i o n s h i p to o t h e r t e r p e n o i d

metabolites

s u g g e s t e d S t r u c t u r e I as a p o s s i b l e structure f o r v i c t o x i n i n e ( F i g u r e 1 ) . T h e s t r u c t u r e w a s c o n f i r m e d b y its p a r t i a l synthesis f r o m p r e h e l m i n t h o sporol (Structure I I ) . Prehelminthosporol was converted into the lactone ( S t r u c t u r e I I I ) a n d t h e n i n t o the d i o l ( S t r u c t u r e I V ) w i t h H t h i u m a l u m i n u m hydride.

A c i d t r e a t m e n t c y c l i z e d S t r u c t u r e I V to t h e s a t u r a t e d

i s o m e r S t r u c t u r e V I . T h e d i m e t h y l sulfonate ( S t r u c t u r e V )

from

Struc

t u r e I V w a s t r e a t e d w i t h e t h a n o l a m i n e i n d i o x a n to g i v e v i c t o x i n i n e . S t r u c t u r e s I V a n d V I w e r e s u b s e q u e n t l y f o u n d as m a j o r metabolites i n c u l t u r e filtrates of D . victoriae

(7).

A m e t a b o l i t e b e l o n g i n g to a c o m p l e t e l y different class of c o m p o u n d s w a s i s o l a t e d i n 1974 f r o m c u l t u r e filtrates of D . victoriae

(8).

The new

m e t a b o l i t e , g l i o v i c t i n V I I , b e l o n g s to a series of m i c r o b i a l s u l f u r - c o n t a i n i n g c o m p o u n d s s u c h as g l i o t o x i n ( S t r u c t u r e V I I I ) a n d s p o r i d e s m i n (Structure I X )

whose origin can be explained b y a

precursor ( F i g u r e 2 ) .

D

diketopiperazine

G h o v i c t i n is n o t as t o x i c as g l i o t o x i n . A p p a r e n t l y

t h e d i s u l f i d e g r o u p p r e s e n t i n g l i o t o x i n is r e s p o n s i b l e for the

difference

i n t o x i c i t y . A l s o m e t h y l a t e d sulfide groups a r e n o t as toxic. T h e p a t h o t o x i n f r o m H. carbonum

( a Drechslera)

causes leaf spots

a n d e a r rots o n c e r t a i n k i n d s of c o r n a n d is t o x i c to s u s c e p t i b l e c o r n at 0.5

mg/ml.

T h e i m p u r e t o x i n is s t a b l e b u t b e c o m e s u n s t a b l e


when

14.

SHOTWELL

321

Helminthosporium

A N D ELLIS

OH SCH 3

OH NCH 3

0


VII.

CH3

CH 2 0H

SCH 3 Gliovictin

IX. Sporidesmin D

VIII. Gliotoxin

Figure 2.

SCH3

Microbial sulfur-containing

compounds

p u r i f i e d a n d c r y s t a l l i z e d a n d loses a c t i v i t y a t — 20 ° C . y i e l d s five n i n h y d r i n - r e a c t i n g c o m p o u n d s :

A c i d hydrolysis

alanine, proline, a n d three

u n i d e n t i f i e d ones. B e c a u s e t h e t o x i n is s o l u b l e i n o r g a n i c solvents, i t i s probably a cyclic peptide ( 9 ) . H e l m i n t h o s p o r o s i d e ( F i g u r e 3 ) is t h e first host-specific p l a n t t o x i n to h a v e a structure ( S t r u c t u r e X ) p r o p o s e d f o r i t ( 1 0 ) . T h e is p r o d u c e d b y H. sacchari

(D. sacchari),

compound

the causal organism of eye

spot disease i n sugar cane. S u g a r c a n e leaves t r e a t e d w i t h t h e p u r e t o x i n e x h i b i t s y m p t o m s i d e n t i c a l t o those p r o d u c e d b y t h e f u n g u s .

A light

g r e e n spot forms, w h i c h d e v e l o p s i n t o r e d d i s h b r o w n r u n n e r s . A c i d h y d r o l y s i s o f h e l m i n t h o s p o r o s i d e r e s u l t e d i n galactose a n d a h y d r o x y l a t e d cyclopropane.

O n the basis o f s p e c t r a l a n d c h e m i c a l p r o p e r t i e s t h e p r o

p o s e d s t r u c t u r e f o r t h e t o x i n is 2 - h y d r o x y c y c l o p r o p y l - a - D - g a l a c t o p y r a n o side ( S t r u c t u r e X ) . A p a t h o t o x i n p r o d u c e d b y H. maydis

(D. maydis)

causes b l i g h t

symptoms o n corn ( I I ) . E v i d e n c e indicates that t h e toxin is a fairly stable, l o w - m o l e c u l a r - w e i g h t p o l y p e p t i d e . S e v e r a l p h y t o t o x i n s h a v e b e e n r e p o r t e d as metabolites o f species o f Helminthosporium. sporium

sativum

( a Drechslera)

Helmintho-

produces a toxin responsible f o r w i d e

s p r e a d s e e d l i n g b l i g h t , foot a n d r o o t rot, a n d l e a f s p o t i n cereals i n N o r t h A m e r i c a t h a t has b r o u g h t a b o u t C a n a d a (12,13).

financial

losses, p a r t i c u l a r l y i n w e s t e r n

T h e toxin helminthosporal (Structure X I ) is not host-

specific ( F i g u r e 4 ) . A c l o s e l y r e l a t e d s e s q u i t e r p e n o i d c o m p o u n d , h e l m i n t h o s p o r o l ( S t r u c t u r e X I I ) , i s also f o r m e d b y H. sativum.

Structure X I

CH20H HO

H X. Helminthosporoside

Figure 3.

2-Hydroxycyclopropyl-a-O-gahctopyranoside, helminthosporiside


322

MYCOTOXINS

XIII. Ri = CH 3 Prehelminthosporol

XI. R = CHO Helminthosporal

XIY. R t = CH 2 0H


XII. R = CH 2 0H Helminthosporol

9-hydroxyprehelminthosporol

Figure 4.

Sesquiterpenoid

compounds

has b e e n d e t e r m i n e d , a n d t h e c o m p o u n d , a d i a l d e h y d e , has b e e n s y n thesized.

Helminthosporol (Structure X I I ) , the compound

in which

o n e o f the a l d e h y d e groups is r e d u c e d t o a n a l c o h o l , stimulates t h e e l o n g a t i o n o f l e a f sheaths o f r i c e seedlings. B i o s y n t h e t i c studies i n d i c a t e t h a t these c o m p o u n d s

are probably

f o r m e d b y nonhead-to-tail l i n k i n g of three terpene units followed b y a c y c l i z a t i o n o f t h e p r e c u r s o r (14).

Probably helminthosporal a n d helmin

t h o s p o r o l d o n o t exist as s u c h i n c u l t u r e l i q u o r s , b u t t h e y are f o r m e d d u r i n g i s o l a t i o n p r o c e d u r e s f r o m acetals o f c o m p o u n d s

d e s i g n a t e d as

prehelminthosporal (Structure X I I I ) a n d prehelminthosporol (Structure II).

Prehelminthosporol a n d 9-hydroxyprehelminthosporol

(Structure

X I V ) h a v e b e e n i s o l a t e d f r o m c u l t u r e filtrates o f fermentations o f bolus

sativus

Cochlio

( I t o et K u r i b a y a s h i ) D r e c h s l e r ex D a s t u r [ t h e p e r f e c t

stage o f H. sativum

( t h e Drechslera

c o n i d i a l state o f C . sativus)']

(15).

P r e h e l m i n t h o s p o r a l has n o t b e e n d e t e c t e d i n c u l t u r e l i q u o r s o f H.

sativum.

S o m e o f t h e first s e c o n d a r y m e t a b o l i t e s o f m o l d s s t u d i e d w e r e t h e polyhydroxyanthraquinone pigments isolated a n d characterized b y Rais t r i c k a n d h i s associates ( 1 6 , 17, 18, 19, 20, 21).

These compounds are

c l o s e l y r e l a t e d ( T a b l e I ) . F o r e x a m p l e t r i t o s p o r i n i s i n d e e d ω-hydroxycatenarin a n d c a n be synthesized f r o m catenarin; cynodontin has been s y n t h e s i z e d f r o m h e l m i n t h o s p o r i n . Helminthosporium

and

Drechslera

strains t h a t p r o d u c e p o l y h y d r o x y a n t h r a q u i n o n e s h a v e b e e n i s o l a t e d as c a u s a t i v e agents o f p l a n t diseases ( T a b l e I ) . T h e c o m p o u n d s a r e h i g h l y colored pigments that

fluoresce

a n d are p r o b a b l y responsible for the

d i s c o l o r a t i o n s n o t i c e d o n diseased leaves.

I n 1974 c h r y s o p h a n o l a n d

emodin, polyhydroxyanthraquinones, were isolated f r o m culture liquors of Drechslera

catenaria

( D r e c h s l . ) I t o (H. catenarium

Drechsler)

These naturally occurring quinones have cathartic properties

(22).

(23).

A p o l y h y d r o x y x a n t h o n e , r a v e n e l i n ( S t r u c t u r e X V , F i g u r e 5 ) , is p r o d u c e d b y H . turcicum b l i g h t , a n d H. ravenelii

(D. turcica),

t h e c a u s a t i v e agent o f n o r t h e r n c o r n

C u r t , [ s y n o n y m o f Drechslera

ravenelii


(Curt.)

14.

SHOTWELL

323

Helminthosporium

A N D ELLIS

OH

OH

0 XV.

OH

Ravenelii)


Figure 5.

Ravenelin

S u b r a m . et J a i n ] , a p a r a s i t e g r o w i n g o n grasses i n N o r t h a n d S o u t h America and i n China (24).

M y y c e l i a of D . leersiae

( A t k . ) S u b r a m . et

J a i n c o n t a i n l u t e o l e e r s i n ( 0 2 β Η 8 θ ) a n d a l b o l e e r s i n (C26H40O7) w h i c h 3

7

are closely related a n d readily interconvertible (25).

L u t e o l e e r s i n is

t h o u g h t to b e a s u b s t i t u t e d q u i n o n e o r s e m i q u i n o n e a n d a l b o l e e r s i n , t h e p h e n o l c o r r e s p o n d i n g to l u t e o l e e r s i n . A l t h o u g h the structures of p o l y h y d r o x y a n t h r a q u i n o n e s a n d hydroxyxanthones compounds

poly

i n d i c a t e p o s s i b l e t o x i c i t y , a c t u a l toxicities of

to a n i m a l s h a v e n e v e r b e e n d e t e r m i n e d .

these

N o information

exists o n the p o s s i b l e effects o n a n i m a l s g r a z i n g o n grasses i n f e c t e d w i t h Drechslera

strains p r o d u c i n g these c o m p o u n d s .

B e c a u s e of the n u m b e r

of a n i m a l deaths a t t r i b u t e d to mycotoxicoses, i t w o u l d b e i m p o r t a n t to d e t e r m i n e w h e t h e r these c o m p o u n d s are r e s p o n s i b l e for a n y deaths or, i f not, a n y t o x i c effects. S e v e r a l m e t a b o l i t e s of species of Helminthosporium

and

Drechslera

h a v e a n t i m i c r o b i a l p r o p e r t i e s a n d w e r e d i s c o v e r e d i n searches f o r n e w antibiotics.

T h e species w e r e s e l e c t e d for s c r e e n i n g p r o g r a m s f o r

new

a n t i b i o t i c s b e c a u s e of t h e i r k n o w n t o x i c i t y against p l a n t s . M e m b e r s o f a f a m i l y of

a n t i b i o t i c s k n o w n as o p h i o b o l i n s

have been

i s o l a t e d as

metabolites of the f u n g i t h a t are r e s p o n s i b l e f o r s o u t h e r n c o r n b l i g h t [Cochliobolus

heterostrophus

b l i g h t [ D . turcica

(Drechsler) Drechsler] and northern corn

( P a s s . ) S u b r a m . et J a i n , t h e c o n i d i a l state of

was

c l a r i f i e d i n a j o i n t p a p e r b y a g r o u p of J a p a n e s e a n d I t a l i a n w o r k e r s

(26)

turcica

Luttrell].

N o m e n c l a t u r e of

Tricho-

the compounds

metasphaen

w h o s t u d i e d t h e m . T h e i r structures a n d b i o l o g i c a l p r o p e r t i e s a r e s u m m a r i z e d i n T a b l e I I . T h e s t r u c t u r e of o p h i o b o l i n A w a s d e t e r m i n e d i n d e p e n d e n t l y b y N o z o e et a l . (27) et a l . ( 2 8 ) .

(Structure X V I ) and by Canonica

N o z o e a n d his c o - w o r k e r s b a s e d t h e i r c o n c l u s i o n s o n x - r a y

c r y s t a l l o g r a p h i c analysis a n d o n i r a n d N M R spectra of t h e

bromo-

m e t h o x y d e r i v a t i v e . C a n o n i c a a n d his associates s t u d i e d N M R , i r , a n d u v s p e c t r a of s e v e r a l d e r i v a t i v e s a n d r e a c t i o n p r o d u c t s . compounds

s t r u c t u r a l l y r e l a t e d to

cultures of Ophiobolus bolus

heterostrophus

heterostrophus Drechsler

(H.

ophiobolin A

were

Three

D r e c h s l e r [ s y n o n y m of maydis

Nisik.

et

other

isolated

from Cochlio

Miyake,


the

324

MYCOTOXINS

T a b l e I. Ο R4


OH

Compound

Rl

II

Ri

II Ο

OH

Rz

J?2

Ri

Color Crystal

and Form

Catenarin

OH

CH

3

OH

Η

deep r e d p l a t e s

Cynodontin

OH

CH

3

Η

OH

bronze p l a t e s

OH

d a r k r e d needles

Η

b r o w n needles

Helminthosporin

Tritisporin

H

OH

CH

3

CH OH 2

Η

OH


14.

SHOTWELL AND ELLIS

325

Helminthosponum


Polyhydroxyanthraquinones

Producing

Species

Drechslera catenaria (Dreschsler) S. I t o Drechslera graminea ( R a b e n h . ex S c h l e c h t . ) S h o e m . [ c o n i d i a l state of Pyrenophora graminea I t o et Kuribayoshi] Helminthosporium velutinum L i n k ex F i c i n u s et S c h u b e r t Helminthosporium tritici-vulgaris N i s i k a d o [Drechslera c o n i d i a l state of Pyrenophora tritici-repentis (Died.) Drechsler] Pénicillium islandicum S o p p Aspergillus amstelodami ( M a n g . ) T h o r n et C h u r c h Drechslera cynodontis ( M a r i g n o n i ) S u b r a m . et J a i n [conidial state of Cochliobolus cynodontis N e l s o n ] Drechslera euchlaenae ( Z i m m . ) S u b r a m . et J a i n Pyrenophora avenae I t o et K u r i b a y a s h i [ c o n i d i a l state is Drechslera avenae ( E i d a m ) S c h a r i f = Helminthosporium avenae E i d a m ] Drechslera victoriae ( M e e h a n et M u r p h y ) S u b r a m . et J a i n [conidial state of Cochliobolus victoriae N e l s o n ] Drechslera graminea ( R a b e n t h . ex Schlecht.) Shoem. Drechslera cynodontis ( M a r i g n o n i ) S u b r a m . et J a i n Drechslera catenaria ( D r e c h s l e r ) S. I t o Helminthosporium tritici-vulgaris N i s i k a d o [a Drechslera, see above] Helminthosporium tritici-vulgaris N i s i k a d o [a Drechslera]

Plant Disease Associated with Producing Species Reference 16,17,18 leaf s t r i p e of b a r l e y

y e l l o w spot disease of w h e a t

parasite on B e r m u d a , d u r b a , a n d teosinte grasses

16,17,19

leaf spot of oats

leaf s t r i p e of b a r l e y

19, ;

parasite on B e r m u d a , d u r b a , a n d teosinte grasses

y e l l o w spot disease of w h e a t y e l l o w spot disease of w h e a t


326

MYCOTOXINS


Table I.

Compound

R\

R

2

Rs

Color Crystal

R*

and Form

Chrysophanol

H

H

CH

3

H

dark yellow leaflets

Emodin

H

OH

CH

3

H

orange needles

Table Ophiobolin

Other Names

XVI


II.

14.

SHOTWELL

327

Helminthosponum

A N D ELLIS


Continued

Producing

Species

Plant Disease Associated with Producing Species Reference

(Drechsler) S. I t o

22,23

Pénicillium islandicum S o p p Trichoderma polysporum ( L i n k ex Pers.) R i f a i [Pachybasium candidum (Sacc.) P e y r o n . ] Drechslera catenaria (Drechsler) S. I t o

22,23

Drechslera

catenaria

Ophiobolins Producing

Organisms

Antimicrobial Activity

Drechslera turica a c t i v e a t levels of (Pass.) S u b r a m . 1-5 M g / m l et J a i n [conidial against state of TrichTrichophyton, ometasphaeria Glomerella, turcica L u t t r e l l ] Gleosporium, Drechslera zizaniae Trichomonas (Nisikado) Subram. vaginalis D o n n e , et J a i n and phytotoxic Drechslera leersiae fungi (Atk.) Subram. et J a i n Drechslera panicimiliacei ( N i s i k a d o ) S u b r a m . et J a i n Cochliobolus heterostrophus (Drechsler) D r e c h s l e r [the s e x u a l stage of Drechslera maydis ( N i s i k . et M i y a k e ) S u b r a m . et J a i n ]

Toxicity to mice, L D : 12 m g / k g i . v . ; 238 m g / k g , s u b cutaneously; 73 m g / k g i . p . 5 0

pathogenic t o rice


Reference 26,27

28,29

328

Ophiobolin B

Other

Names

zizanin


ophiobolosin A

zizanin B

cochliobolin B

HO

C H

3

XVII

CH

zizanin A

D

3

cephalonic a c i d

CH

3

XIX


14.

SHOTWELL AND ELLIS

329

Helminthosporium

Continued


Producing

Organisms

Cochliobolus heterostrophus (Drechsler) Drechsler Drechslera zizaniae (Nisikado) Subram. et J a i n Cochliobolus miyabeanus (S. I t o et K u r i bayashi) Drechsler ex D a s t u r [ c o n i d i a l state is Drechslera oryzae ( B r e d a de Haan) Subram. et J a i n Drechslera zizaniae (Nisikado) Subram. et J a i n

Cephalosporium caerulens Matsuamae, K a m i o et H a t a [name n o t v a l i d l y published]


Toxicity

to mice, LD50: active against 4.4 m g / k g i . p . Trichophyton interdigitale, Macrosporium bataticola, Glomerella fructigena, and Gleosporium kaki p a t h o g e n i c t o rice

Reference 29,30

31,32

31

Slightly active against Staphylococcus aureus Rosenbach


33,34

330

MYCOTOXINS

c o n i d i a l s t a t e ) ] a n d D . zizaniae

Drechslera

(29, 30, 31, 3 2 ) . C

( N i s i k a d o ) S u b r a m . et J a i n

These were ophiobolin Β (Structure X V I I ) , ophiobolin

(Structure X V I I I ) , and anhydroophiobolin.

l a t e d f r o m the m y c e l i u m of bayashi) Haan)

Cochliobolus

Ophiobolosin Β was iso (Ito

miyabeanus

D r e c h s l e r ex D a s t u r [ c o n i d i a l state is D . oryzae Subram.

et

Jain]

which

also

formed

et

Kuri-

(Breda

ophiobolin

Β

de

(32).

A l t h o u g h the structure of o p h i o b o l o s i n Β has n o t b e e n e l a b o r a t e d , t h e


c o m p o u n d has the same effect o n r i c e seedlings a n d f u n g i as o p h i o b o l i n B . C e p h a l o n i c a c i d ( S t r u c t u r e X I X ) , a c o m p o u n d closely r e l a t e d t o the o p h i o b o l i n s , has b e e n i s o l a t e d as a m i n o r m e t a b o l i t e of M a t s u a m a e , K a m i o et

caerulens (Table II)

Hata

Cephalosporium

(name not v a l i d l y

published)

(33,34).

T h e n o v e l skeletons of the o p h i o b o l i n s are f o r m e d b i o s y n t h e t i c a l l y b y t h e h e a d - t o - t a i l c o n d e n s a t i o n of five i s o p r e n e u n i t s ( 3 5 ) . the first examples of C skeleton w a s

2 5

terpenoids.

established b y

m e d i u m containing

(2- C) 1 4

T h e s e are

E v i d e n c e for t h e f o r m a t i o n o f t h e

c u l t u r i n g C. mevalonic

in a

miyabeanus

acid lactone

(14).

synthetic

Labels

ap

p e a r e d i n carbons 4, 8 , 1 2 , 1 6 , a n d 24 ( o r 2 5 ) i n o p h i o b o l i n A ( F i g u r e 6 ) . B o t h N o z o e et a l . ( 3 5 ) a n d C a n o n i c a (14)

proposed that i n the biosyn

thesis of o p h i o b o l i n A a n d Β m o l e c u l a r o x y g e n m a y b e d i r e c t l y i n c o r p o 23

*

18

25

i>

0

OH XVI.

OH

CH 3

20

Ophiobolin A

XXI.

Getanylnerolidol

CH 3 XH3

OH XX.

CH 3

Precursors

Figure 6.

Compounds involved in biosynthesis of

ophiobolins



14.

SHOTWELL

331

Helminthosporium

A N D ELLIS

XXII. Ri = R 3 = H; R 2 = OH; R4 = OAc Cochlioquinone A XXIII. Ri =

R2

= H;

R3R4 =

Figure 7.

0 Cochlioquinone Β

Cochlioquinones

r a t e d i n t o the C 1 4 a n d t h a t the o x y g e n o n t h e C 3 comes f r o m t h e m e d i u m . T h e p a t h w a y f o r t h e f o r m a t i o n of o p h i o b o l i n s i s p r e c u r s o r Structures X X - > X V I I I - » X V I I - » X V I . T h e p r o b a b l e course o f c y c l i z a t i o n o f t h e biological equivalent of geranyl farnesyl pyrophosphate was studied b y incorporating

tritium-labeled a n d doubly

labeled

(tritium

m e v a l o n i c a c i d lactone i n t o fermentations o f C. miyabeanus strophus

and

1 4

C)

a n d C. hetero

(14, 36).

T w o compounds, geranylnerolidol (Structure X X I ) a n d a proposed precursor of the ophiobolins C. heterostrophus

(37).

(Structure X X ) , have been isolated from

I n the same s t u d y N o z o e a n d c o - w o r k e r s d e t e c t e d

b y g a s - l i q u i d c h r o m a t o g r a p h y d i t e r p e n e a n d sesterterpene h y d r o c a r b o n s , a sesterterpene a l c o h o l , a n d squalene. A n y o n e o f these c o m p o u n d s

could

b e i n v o l v e d i n t h e biosynthesis o f o p h i o b o l i n s . W h e n the m o l d that produces

t h e o p h i o b o l i n s , C. miyabeanus,

is

g r o w n under suitable conditions, t w o y e l l o w pigments c a n be isolated f r o m t h e m y c e l i u m a n d m e d i u m (38).

These pigments can be extracted

w i t h hexane a n d p u r i f i e d b y f r a c t i o n a l c r y s t a l l i z a t i o n a n d c h r o m a t o g r a phy.

Structures X X I I a n d X X I I I

( F i g u r e 7 ) were established for the

t w o p i g m e n t s c o c h l i o q u i n o n e s A a n d Β b y c h e m i c a l , spectroscopic, a n d crystallographic evidence. terpenoid unit.

Cochlioquinones A a n d Β contain a sesqui-

Studies s h o w t h a t t h e b i o s y n t h e s i s o f A a n d Β occurs

t h r o u g h t h e i n t r o d u c t i o n o f a f a r n e s y l u n i t onto a n a r o m a t i c p r e c u r s o r L a b e l e d m e v a l o n i c a c i d lactone is i n c o r p o r a t e d e x c l u s i v e l y i n t o

(39).

t h e C15 t e r p e n o i d u n i t ( R i n g s A , B , a n d C ) . T h e n o n t e r p e n o i d p r e c u r s o r is a r o m a t i c a n d has s e c o n d a r y m e t h y l g r o u p s d e r i v e d f r o m m e t h i o n i n e . I n s c r e e n i n g Helminthosporium

a n d Drechslera

species

pathogenic

to p l a n t s f o r a n t i m i c r o b i a l a c t i v i t y , s e v e r a l m e t a b o l i t e s other t h a n t h e ophiobolins have been isolated a n d described ( T a b l e I I I ) . avenae

I t o et K u r i b a y a s h i

Drechslera

[ H . avenae

c o n i d i a l state, D. avenae

Eidam

Pyrenophora

is a s y n o n y m

of the

( E i d a m ) Scharif], a pathogen of


332

MYCOTOXINS

Table III. Metabolite

Structure CH

Siccanin


Metabolites of

CH

3

^

3

CH

3

CH XXIV

Helmintin

CiiH 0 N2 8

2


14.

SHOTWELL AND ELLIS

333

Helminthosporium

Helminthosporium Species


Producing

Organisms


Toxicity

Reference

Pyrenophora avenae I t o et K u r i b a y a s h i [conidial state is Drechslera avenae ( E i d a m ) S c h a r i f = H. avenae Eidam] Drechslera siccans (Drechsler) Shoem.

Tichophyton, 0.1 M g / m l Gibberella, Aspergilli, Penicillia, Alternaria; 5-12 / i g / m l

Drechslera siccans (Drechsler) Shoem.

Trichophyton, 5 Mg/ml Microsporum gypseum (Bodin) Guiart et G r i g o r a k i s , 10 M g / m l ; Rhizopus stolonifer ( E h r e n b . ex F r . ) V u i l l . [R. nigricans Ehrenb.], 10 j u g / m l a n t i t u m o r , some LD50 for m i c e : yeast, pathogenic 44.1 m g / k g i . p . plant fungi, Trichomonas

4®

inhibits powdery m i l d e w (Erysiphe graminis D C . ) of w h e a t

45

Pyrenophora avenae I t o et K u r i b a y a s h i (see a b o v e )

Drechslera monoceras (Drechsler) S u b r a m . et J a i n

n o adverse effect i n mice at 500 m g / k g i . p .

40,41

4&i 44


334

MYCOTOXINS

Table III. Structure

Metabolite N=C—NH I I CH C—N

3'-Amino3'-deoxyadenosine

2

v


CH C

OH OH C—CH OH - c — C ^ Η Η NH Η

N—C—Ν

2

2

XXVII Heveadride

CH3CH2

CH3CH2CH2 Ο

Q

//

XXVIII oats, forms XXV).

siccanin

Drechslera

(Structure X X I V ) (Drechsler)

siccans

and pyrenophorin

(Structure

Shoem., the fungus

responsible

f o r l e a f s p o t o n r y e grass, f o r m s s i c c a n i n a n d h e l m i n t i n . p o u n d s s u c h as m o n o c e r i n

(Structure X X V I ) ,

Other

com

3'-amino-3'-deoxyadeno-

sine (Structure X X V I I ) , a n d heveadride (Structure X X V I I I ) have been i s o l a t e d f r o m c u l t u r e filtrates a n d m y c e l i u m of Helminthosporium (Table

III).

Heveadride

species

( S t r u c t u r e X X V I I I ) is a n i s o m e r of

bysso-

chlamic acid. T h e b i o s y n t h e t i c p a t h w a y of s i c c a n i n ( S t r u c t u r e X X I V ) e s t a b l i s h e d t h r o u g h i n t a c t a n d cell-free systems of D . siccans S h o e m . (49) of

(Figure 8).

I t i n v o l v e s the f o l l o w i n g steps: ( a )

frarw-y-monocyclofarnesol

(Structure X X I X )

l a c t o n e or f a r n e s y l p y r o p h o s p h a t e ;

(b)

from

acid

(Structure X X X )

into

Formation

mevalonic

acid

c o u p l i n g r e a c t i o n of t h e t e r p e n i c

p r e c u r s o r w i t h o r s e l l i n i c a c i d ; ( c ) o x i d a t i v e c o n v e r s i o n of menic

has b e e n

(Drechsler)

siccanochromenic

presiccanochroacid

(Structure


14.

SHOTWELL

335

Helminthosporium

A N D ELLIS

Continued Producing

Helminthosporium



Organisms sp.

Toxicity

Antitumor, i n h i b i t s yeast

Reference

LD for m i c e : 28 m g / k g i . p .

46,47

5 0

48

XXXI);

(d)

decarboxylation

(Structure X X X I I ) , and (e)

of S t r u c t u r e X X X I to s i c c a n o c h r o m e n e p o x y - o l e f i n t y p e of c y c l i z a t i o n of

A

siccano

c h r o m e n Β ( S t r u c t u r e X X X I I I ) to s i c c a n i n . T h e precursors of s i c c a n i n have previously been isolated from ( s y n o n y m of D. siccans)

cultures of H.

siccans

d u r i n g b i o s y n t h e t i c studies a n d

Dreschler

characterized

as t r i p r e n y l p h e n o l derivatives. T h e y i n c l u d e Structures X X X ( 5 0 ) , (51),

X X X I I , a n d X X X I I I (52,53).

Previously

XXXI

irans-a-monocyclofarnesol

has b e e n i s o l a t e d as a m i n o r constituent of H. siccans

mycelia

(54).

Sterigmatocystin (Structure X X X I V , F i g u r e 9 ) , a carcinogenic p o u n d s t r u c t u r a l l y r e l a t e d to the aflatoxins, w a s r e p o r t e d to b e b y a n u n i d e n t i f i e d species of Bipoforis A u c a m p a n d H o l z a p f e l (56) quinones—bipolarin

(Structure

averufanin

b y H o l z a p f e l et al

discovered

that t h r e e

XXXV),

(Structure

com

produced I n 1970

(55).

polyhydroxyanthra

versicolorin

XXXVII)—were

C

(Structure

XXXVI),

and

produced

Bipolaris.

I n t h e same s t u d y c u r v u l a r i n ( S t r u c t u r e X X X V I I I ) , a m a c r o -


by

336

MYCOTOXINS

COOH


XXIX.

trans r-monocyclofarnesol

XXX.

Presiccanochroneiic

acid

R

XXXI. R = COOH, Siccanochromenic acid

XXXIII. S i c c a n o c h r o m e i Β

XXXII. R = Η , Siccanochromen A

Figure 8.

Precursors of siccanin

c y c l i c l a c t o n e , w a s also i s o l a t e d f r o m Bipolaris. b e e n k n o w n as a m e t a b o l i t e o f Aspergillus

Sterigmatocystin has

versicolor ( V u i l L ) T i r a b o s c h i .

V e r s i c o l o r i n C i s p r o d u c e d b y A . flhvus L i n k ex F r . , A . versicolor, a n d A . nidulans

( E i d a m ) W i n t . These compounds

a r e significant b e c a u s e

t h e i r b i o s y n t h e t i c p a t h w a y s a r e closely r e l a t e d t o those o f the aflatoxins, p o t e n t c a r c i n o g e n s e l a b o r a t e d b y strains o f t h e A . flavus series. Versicolorin C , a n orange-red pigment, a n d averufanin have b e e n i s o l a t e d as m e t a b o l i t e s f r o m a s t r a i n o f A . flavus that

also

produces

aflatoxin B i (Structure X X X I X ) ( 5 7 ) . A u c a m p a n d H o l z a p f e l ( 5 6 ) p r o posed

that bipolarin m a y bridge

t h e g a p i n biosynthetic

pathways

between a hypothetical C i - p o l y k e t i d e o n the one h a n d and versicolorin 8

C , s t e r i g m a t o c y s t i n , a n d aflatoxin B i o n t h e other. T h e p o l y k e t i d e w o u l d b e f o r m e d b y t h e c o n d e n s a t i o n o f acetate u n i t s after w h i c h i t w o u l d c y c l i z e t o a n a n t h r a q u i n o n e ( 5 8 ) . I n 1973 t h e c o n v e r s i o n o f s t e r i g m a t o c y s t i n t o a f l a t o x i n B i b y t h e r e s t i n g m y c e l i u m o f A . parasiticus

Speare

was reported ( 5 9 ) . S t e r i g m a t o c y s t i n w a s p r o d u c e d b y Bipolaris

o n corn meal i n yields

as g r e a t as 1.2 g / k g . T h i s h i g h y i e l d raises t h e p o s s i b i l i t y that s t e r i g m a t o c y s t i n c o u l d b e a dangerous

mycotoxin.

The L D

5 0

of the mycotoxin

administered intraperitoneally i n d i m e t h y l sulfoxide or wheat germ o i l w a s 6 0 - 6 5 m g / k g i n a l b i n o rats. N e c r o s i s o f k i d n e y a n d l i v e r cells w a s


14.

337

Helminthosporium

S H O T W E L L AND ELLIS

r e v e a l e d b y h i s t o p a t h o l o g i c a l e x a m i n a t i o n s o f tissues

(55). Another

s t u d y (60) s h o w e d t h a t s t e r i g m a t o c y s t i n c a u s e d n o t o n l y l o c a l sarcomas b u t also l i v e r t u m o r s a n d h a d a b o u t 1 / 1 0 0 - 1 / 2 5 0 o f t h e a c t i v i t y o f aflatoxin.

Subcutaneous injections o f s t e r i g m a t o c y s t i n i n rats ( 0 . 5 m g

t w i c e w e e l d y f o r 2 4 w e e k s ) i n d u c e d l o c a l sarcomas a n d a f t e r 4 7 w e e k s i n d u c e d l i v e r tumors i n t w o rats. L a r g e doses o f aflatoxin B i s u b c u t a n e ously d i d not produce liver tumors although they caused m a n y m o r e l o c a l


sarcomas.

O r a l a d m i n i s t r a t i o n o f s t e r i g m a t o c y s t i n also p r o d u c e d

t u m o r s i n rats (61).

liver

T u m o r s o f o t h e r types w e r e n o t i c e d .

B e s i d e s sterigmatocystin o n e other m y c o t o x i n h a s b e e n r e p o r t e d as a p r o d u c t o f Helminthosporium f a c t b e several toxic c o m p o u n d s . m e d i u m b y H. carbonum

T h e unknown mycotoxin may i n

(62).

I t is f o r m e d o n a h i g h - p r o t e i n c e r e a l

( a Drechslera)

a n d is toxic t o m i c e .

Cytochalasins A (Structure X L ) , Β (Structure X L I ) , a n d F (Struc t u r e X L I I ) p r o d u c e d b y H. dematioideum n y m o f D. dematioidea

B u b â k et W r o b l e w s k i

( B u b . et W r o b . )

[syno

S u b r a m . et J a i n ]

(Figure

10) b e l o n g to a series o f r e l a t e d b i o l o g i c a l l y a c t i v e c o m p o u n d s

studied

b y g r o u p s i n three countries. T h e c o m p o u n d s h a v e a n effect o n c e l l u l a r functions a n d morphology a n d are considered to b e mycotoxins.

OH XXXIV.

OH

0

0

0CH3

ο

Sterigmatocystin

XXXV.

OH

XXXVI. Versicolorin G

Bipolarin

0 XXXVII.

Averufanin

0

XXXVH1. Curvularin

Figure

XXXIX.

0

Aflatoxin B i

9. Helminthosporium metabolites with thetic pathways related to aflatoxin 2^

biosyn


They

338

MYCOTOXINS

0 XL. XLI.


ο

0

R = 0 Cytochalasin A R = H.OH

Cytochalasin F

XLV.

Cytochalasin

Cytochalasin Β

XLIII. C y t o c h a l a s i n

XLIX.

0

XLII.

Cytochalasin D

Figure 10.

C

Ε

Cytochalasins

are characterized b y a substituted, hydrogenated

isoindole group to

w h i c h i s f u s e d a m a c r o c y c l i c r i n g that i s either a c a r b o c y c l i c c o m p o u n d , a lactone, o r a cyclic carbonate.

T h e metabolites isolated b y the Swiss

f r o m a Phoma species h a v e b e e n c a l l e d p h o m i n s .

Those from

Zt/go-

sporium masonii H u g h e s w e r e n a m e d z y g o s p o r i n s b y the Japanese. T h e E n g l i s h d e s c r i b e d t h e i r m e t a b o l i t e s f r o m Helminthosporium cytochalasins

(cytos = cell;

chalasis == r e l a x a t i o n ) .

species as

T h e three

proposed a systematic nomenclature based o n the generic name

groups cyto-

chalasan f o r the cytochalasins, phomins, a n d zygosporins ( 6 3 ) . P h o m i n ( p h o m i n e , c y t o c h a l a s i n B ) , t h e first c y t o c h a l a s i n r e p o r t e d , w a s d e s c r i b e d i n 1966 as a m a c r o l i d e a n t i b i o t i c w i t h c y t o s t a t i c a c t i v i t y p r o d u c e d b y a Phoma species (64). L a t e r i n a m o r e d e t a i l e d i n v e s t i g a t i o n o f the Phoma m e t a b o l i t e s a c l o s e l y r e l a t e d c o m p o u n d w i t h s i m i l a r a c t i v i t y , d e h y d r o p h o m i n (cytochalasin A ) , w a s isolated ( 6 5 ) . Structures were first d e t e r m i n e d b y a series o f d e g r a d a t i o n s ; l a t e r i r , N M R , a n d mass


14.

SHOTWELL

spectroscopy

339

Helminthosporium

A N D ELLIS

of the c o m p o u n d s

c o n f i r m e d these d e g r a d a t i o n

X - r a y analysis of t h e p h o m i n - s i l v e r

fluoroborate

a b s o l u t e stereochemistry of p h o m i n

products.

c o m p l e x e s t a b l i s h e d the

(66).

I n 1967 A l d r i d g e a n d c o - w o r k e r s ( 6 7 ) i s o l a t e d c y t o c h a l a s i n s A a n d Β f r o m H. dematioideum

(Drechslera

Metarrhizium

( M e t s c h . ) Sorok. S u b s e q u e n t l y t h e y e s t a b l i s h e d

anisopliae

and C and D

dematioidea)

Structures X L a n d X L I as the structures of A a n d Β ( 6 8 ) .

from

C . T a m m of

Basel, Switzerland a n d D . C . Aldridge's group determined the structure Downloaded by KTH ROYAL INST OF TECHNOLOGY on June 7, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch014

of c y t o c h a l a s i n Β ( p h o m i n )

a b o u t t h e same t i m e b a s e d o n almost c o m

p l e t e l y i n d e p e n d e n t evidence, b u t the d e g r a d a t i o n s t h e y d e s i g n e d fered.

Earlier

a F r e n c h patent reported

p r o d u c e d b y H. dematioideum nitrogen.

(Drechslera

two

fungicidal

dematioidea)

dif

compounds

that contained

T h e y w e r e i n t r a c o n v e r t i b l e b y o x i d a t i o n - r e d u c t i o n reactions,

h a d the e m p i r i c a l f o r m u l a s of C29H35NO5 a n d C29H37NO5, a n d a l m o s t certainly were cytochalasins A a n d Β

(69).

C y t o c h a l a s i n s C a n d D are p r o d u c e d i n l o w y i e l d s b y M.

anisopliae

a n d are difficult to separate. B e c a u s e h e h a d p a r t i c u l a r d i f f i c u l t y o b t a i n i n g c y t o c h a l a s i n D , almost a l l of A l d r i d g e ' s d e g r a d a t i v e studies d o n e o n C (70). and D

( S t r u c t u r e X L I V ) h a v e l a c t o n e g r o u p s i n the m a c r o c y c l i c r i n g .

S i m u l t a n e o u s l y M i n a t o a n d M a t s u m o t o (71)

r e p o r t e d t h e i s o l a t i o n of a

c y t o t o x i c a n t i b i o t i c , z y g o s p o r i n A , f r o m c u l t u r e filtrates of masonii.

were

H e d e t e r m i n e d t h a t cytochalasins C ( S t r u c t u r e X L I I I )

Zygosporium

T h e i r studies r e v e a l e d S t r u c t u r e X L I V f o r z y g o s p o r i n A w h i c h

is i d e n t i c a l to c y t o c h a l a s i n D . L a t e r M i n a t o a n d K a t a y a m a (72) a n d c h a r a c t e r i z e d m i n o r m e t a b o l i t e s of Z . masonii,

isolated

zygosporins D , E , F ,

a n d G t h a t w e r e r e l a t e d to t h e cytochalasins i n s t r u c t u r e a n d b i o l o g i c a l activity. Structures w e r e p r o p o s e d i n 1972 for c y t o c h a l a s i n Ε p r o d u c e d Rosellinia

necatrix

of H. dematioideum

by

( H a r t i g ) B e r l . et P r i l l , a n d for F , a m i n o r m e t a b o l i t e (Drechslera

dematioidea)

(73).

S i n c e t h e n alternate

structures t h a t seem correct h a v e b e e n e s t a b l i s h e d f o r c y t o c h a l a s i n (Structure X L V ) and F (Structure X L I I )

(74).

Ε

T h e cyclohexane rings

i n Ε a n d F c o n t a i n epoxides r a t h e r t h a n t h e p r e v i o u s l y suggested

double

b o n d a n d h y d r o x y l g r o u p . P e r h a p s m o r e i m p o r t a n t l y , the c y t o c h a l a s i n Ε studied was

produced

b y Aspergillus

clavatus

D e s m . collected

from

m o l d - d a m a g e d r i c e i n a T h a i h o u s e h o l d w h e r e a y o u n g b o y d i e d of a n u n i d e n t i f i e d toxicosis. w i t h A . clavatus

T h e cytochalasin Ε produced on rice inoculated

had an L D

5 0

i n rats of 2.6 m g / k g i . p . or 9.1 m g / k g o r a l l y .

D e a t h i n m i c e w a s a t t r i b u t e d to c i r c u l a t o r y c o l l a p s e c a u s e d b y m a s s i v e e x t r a v a s c u l a r effusion of p l a s m a . I n I n d i a a c o m p o u n d t h a t is c o n s i d e r e d closely r e l a t e d t o c y t o c h a l a s i n D w a s p r o d u c e d b y a n e w l y i d e n t i f i e d f u n g u s , Phomopsis (name not validly published) (75).

paspali

Pendse

T h e fungus h a d been isolated f r o m


340

MYCOTOXINS

the f o o d g r a i n , m i l l e t (Paspalum

L i n n . ) , w h i c h is con

scrobiculatum

s u m e d b y t h e p o o r e s t section of t h e r u r a l p o p u l a t i o n . T h e g r a i n s t o x i c i t y to m a n a n d a n i m a l s has b e e n k n o w n f o r centuries, a n d extracts r e p o r t e d l y h a v e a t r a n q u i l i z i n g effect o n a n i m a l s . B h i d e a n d P e n d s e also r e p o r t e d t h a t c y t o c h a l a s i n s g i v e n b y i p i n j e c t i o n to dogs a t 1-2 m g / k g

produced

t r a n q u i l i t y a l o n g w i t h tremors a n d depressed m o t o r a c t i v i t y . C y t o c h a l a s i n s affect c e l l u l a r f u n c t i o n s a n d possess t e r a t o g e n i c p r o p


erties t h a t m a y present p o t e n t i a l h a z a r d s to a n i m a l s a n d m a n . So m a n y studies h a v e b e e n m a d e o n t h e b i o l o g i c a l p r o p e r t i e s of cytochalasins t h a t a c o m p l e t e p r e s e n t a t i o n c a n n o t b e m a d e here.

T h e activities o f c y t o

chalasins A , B , C , a n d D a r e essentially s i m i l a r b u t v a r y i n p o t e n c y . A l m o s t a l l w o r k has b e e n o n Β b e c a u s e i t is m o r e a v a i l a b l e t h a n A , C , a n d D . C a r t e r (76) first f o u n d t h a t cytochalasins i n h i b i t m o v e m e n t a n d c y t o p l a s m i c c l e a v a g e i n c u l t u r e d cells l e a d i n g to m u l t i n u c l e a t e d cells. A t h i g h e r concentrations n u c l e a r e x t r u s i o n takes p l a c e . T h e effect o f c y t o c h a l a s i n Β o n m o r p h o g e n e s i s

has b e e n

s t u d i e d w i t h m o u s e s a l i v a r y - g l a n d e p i t h e l i u m cells (77), o n i o n roots ( 7 9 ) , a n d t h e w a t e r m o l d Achlya

(78),

further

mouse embryos

ambisexualis

J . R.

R a p e r ( S O ) . E m b r y o n i c d e v e l o p m e n t of m i c e cells w a s e x t r e m e l y l i m i t e d after c y t o c h a l a s i n t r e a t m e n t a n d d i d n o t p r o c e e d D e f e n d i a n d Stoker (81)

into

organogenesis.

studied the general p o l y p l o i d produced

by

c y t o c h a l a s i n B . C y t o c h a l a s i n s also affect hexose a n d sucrose t r a n s p o r t i n cells (82, 83, 8 4 ) . E a r l i e r W e s s e l s a n d c o - w o r k e r s ( 8 5 ) s u m m a r i z e d t h e effects of c y t o c h a l a s i n o n m i c r o f i l a m e n t s i n c e l l u l a r a n d d e v e l o p m e n t a l processes. O n e r e p o r t has b e e n m a d e o n t h e m o d e o f a c t i o n o f t r i t i u m l a b e l e d c y t o c h a l a s i n Β o f h i g h specific a c t i v i t y

(86).

T h e cytochalasins m a y b e one o f t h e m o r e i m p o r t a n t m y c o t o x i n s , a n d t h e extent to w h i c h t h e y present a p r o b l e m to m a n a n d a n i m a l s should be evaluated. T h e work i n T h a i l a n d on cytochalasin Ε (74) a n d i n I n d i a o n c y t o c h a l a s i n D ( 7 5 ) i m p l i c a t e s t h e m as p o s s i b l y o c c u r r i n g n a t u r a l l y o n foods t h a t c o m p r i s e a n i m p o r t a n t p a r t o f t h e diets o f p e o p l e i n these countries.

W h e n cases of m y c o t o x i c o s i s

arise, c o n s i d e r a t i o n

s h o u l d b e g i v e n t o t h e c y t o c h a l a s i n s as causative agents. M o s t o f t h e a n t i b i o t i c s d e s c r i b e d as b e i n g p r o d u c e d b y sporium

a n d Drechslera

Helmintho

species are k n o w n to b e t o x i c — t o o t o x i c to b e

u s e f u l t h e r a p e u t i c a l l y . T h e s e a n t i b i o t i c s m i g h t t u r n o u t to b e m y c o t o x i n s . O f t h e m y c o t o x i n s n o w c o n s i d e r e d to present serious p r o b l e m s , several w e r e o r i g i n a l l y d e s c r i b e d as toxic a n t i b i o t i c s (e.g., p a t u l i n a n d p e n i c i l l i c acid). Literature

Cited

1. Scott, P. M., Somers, E., J. Agric. Food Chem. (1969) 17, 430-436.


14.

SHOTWELL

AND

Helminthosporium

ELLIS

2. Hesseltine, C. W., Ellis, J. J., Shotwell, O. L., J. Agric. Food Chem. (1971) 19, 707-717. 3. Wood, R. K. S., Ballio, Α., Graniti, Α., "Phytotoxins in Plant Disease," Academic, New York, 1972. 4. Scheffer, R. P., Samaddar K. R , Recent Advan. Phytochem. (1970) 3, 123-142. 5. Pringle, R. B., Braun, A. C., Phytopathology (1960) 50, 324-325. 6. Scheffer, R. P., Pringle, R. B., Phytopathology (1963) 53, 558-561. 7. Dorn, F., Arigoni, D., Chem. Commun. (1972) 1342-1343. 8. Dorn, F., Arigoni, D., Experientia (1974) 30, 134-135. 9. Pringle, R. B., "Phytotoxins in Plant Disease," R. K. S. Wood, A. Ballio, A. Graniti, Eds., pp. 146-151, Academic, New York, 1972. 10. Steiner, G. W., Strobel, G. Α., J. Biol. Chem. (1971) 246, 4350-4357. 11. Smedegard-Petersen, V., Nelson, R. R., Can. J. Bot. (1969) 47, 951-957. 12. de Mayo, P., Spencer, Ε. Y., White, R. W., J. Amer. Chem. Soc. (1962) 84, 494-495. 13. Spencer, E. Y., Ludwig, R. Α., de Mayo, P., White, R. W., Williams, R. E., ADVAN. CHEM. SER. (1966) 53, 106-111. 14. Canonica, L., "Phytotoxins In Plant Disease," R. K. S. Wood, A. Ballio, A. Graniti, Eds., pp. 157-173, Academic, New York, 1972. 15. Aldridge, D. C., Turner, W. B., J. Chem. Soc. (C) (1970) 686-688. 16. Raistrick, H., Robinson, R., Todd, A. R , Biochem. J. (1934) 28, 559-572. 17. Anslow, W. K., Raistrick, H., Biochem. J. (1940) 34, 1124-1133. 18. Anslow, W. K., Raistrick, H., Biochem. J. (1941) 35, 1006-1010. 19. Raistrick, H., Robinson, R., Todd, A. B., Biochem. J. (1933) 27, 1170-1175. 20. Charles, J. H . V., Raistrick, H., Robinson, R., Todd, A. R., Biochem. J. (1933) 27, 499-511. 21. Neelakantan, S., Pocker, Α., Raistrick, H., Biochem. J. (1956) 64, 464-469. 22. van Eijk, G. W., Phytochem. Rep. (1974) 13, 650. 23. Thomson, R. H., "Naturally Occurring Quinones," pp. 179, 191, Academic, New York, 1957. 24. Raistrick, H., Robinson, R., White, D. E., Biochem. J. (1936) 30, 13031304. 25. Ashley, J. N., Raistrick, H., Biochem. J. (1938) 32, 449-454. 26. Tsuda, K., Nozoe, S., Morisaki, M., Hirai, K., Itai, Α., Okuda, S., Canonica, L., Fiecchi, Α., Galli Kienle, M., Scala, Α., Tetrahedron Lett. (1967) 3369-3370. 27. Nozoe, S., Morisaki, M., Tsuda, K., Iitaka, Y., Takahashi, N., Tamura, S., Ishibashi, K., Shirasaka, M., J. Amer. Chem. Soc. (1965) 87, 4968-4970. 28. Canonica, L., Fiecchi, Α., Galli Kienle, M., Scala, Α., Tetrahedron Lett. (1966) 1211-1218. 29. Canonica, L., Fiecchi, Α., Galli Kienle, M., Scala, Α., Tetrahedron Lett. (1966) 1329-1333. 30. Ishibashi, K., J. Antibiot. Ser. A (1962) 15, 88-92. 31. Nozoe, S., Hirai, K., Tsuda, K., Tetrahedron Lett. (1966) 2211-2216. 32. Ohkawa, H., Tamura, T., Agric. Biol. Chem. (1966) 30, 285-291. 33. Itai, Α., Nozoe, S., Tsuda, K., Okuda, S., Iitaka, Y., Nakayama, Y., Tetra hedron Lett. (1967) 4111-4112. 34. Nozoe, S., Itai, A., Tsuda, K., Okuda, S., Tetrahedron Lett. (1967) 41134117. 35. Nozoe, S., Morisaki, M., Tsuda, K., Okuda, S., Tetrahedron Lett. (1967) 3365-3368. 36. Nozoe, S., Morisaki, M., Okuda, S., Tsuda, K., Tetrahedron Lett. (1968) 2347-2349. 37. Nozoe, S., Morisaki, M., Fukushima, K., Okuda, S., Tetrahedron Lett. (1968) 4457-4458. 2


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38. Carruthers, J. R., Cerrini, S., Fedeli, W., Casinovi, C. G., Galeffi, C., Torracca Vaccaro, A. M., Chem. Commun. (1971) 164-166. 39. Canonica, L., Ranzi, B. M., Rindone, B., Scala, Α., Scolastico, C., Chem. Commun. (1973) 213-214. 40. Ishibashi, K., J. Antibiot., Ser. A (1962) 15, 161-167. 41. Hirai, K., Nozoe, S., Tsuda, K., Iitaka, Y., Ishibashi, K., Shirasaka, M . , Tetrahedron Lett. (1967) 2177-2179. 42. Inagaki, N., Chem. Pharm. Bull. (Japan) (1962) 10, 152-154. 43. Ishibashi, K., J. Agric. Chem. Soc. Jap. (1961) 35, 257-262. 44. Nozoe, S., Hirai, K., Tsuda, K., Ishibashi, K., Shirasaka, M., Grove, J. F., Tetrahedron Lett. (1965) 4675-4677. 45. Aldridge, D. C., Turner, W. B., J. Chem. Soc. C (1970) 2598-2600. 46. Gerber, Ν. N., Lechevalier, Η. Α., J. Org. Chem. (1962) 27, 1731-1732. 47. Pugh, L. H., Lechevalier, Η. Α., Solotorovsky, M., Antibiot. Chemother. (1962) 12, 310-317. 48. Crane, R. I., Heddon, P., MacMillan, J., Turner, W. B., J. Chem. Soc., Perkin Trans. 1 (1973) 194-200. 49. Suzuki, K. T., Nozoe, S., Bioorg. Chem. (1974) 3, 72-80. 50. Nozoe, S., Suzuki, K. T., Tetrahedron Lett. (1969) 2457-2460. 51. Shoyama, Y., Yamauchi, T., Nishioka, I., Chem. Pharm. Bull. (Jap.) (1970) 18, 1327. 52. Nozoe, S., Suzuki, K. T., Okuda, S., Tetrahedron Lett. (1968) 3643-3646. 53. Nozoe, S., Suzuki, K. T., Tetrahedron (1971) 27, 6063-6071. 54. Suzuki, K. T., Suzuki, N., Nozoe, S., Chem. Commun. (1971) 527. 55. Holzapfel, C. W., Purchase, I. F. H., Steyn, P. S., Gouws, L., S. Afr. Med. J. (1966) 40, 1110-1111. 56. Aucamp, P. J., Holzapfel, C. W., J. S. Afr. Chem. Inst. (1970) 23, 40-56. 57. Heathcote, J. G., Dutton, M. F., Tetrahedron (1969) 25, 1497-1500. 58. Heathcote, J. G., Dutton, M. F., Hibbert, T. R., Chem. Ind. (1973) 10271030. 59. Hsieh, D. P. H., Lin, M. T., Yao, R. C., Biochem. Biophys. Res. Commun. (1973) 52, 992-997. 60. Dickens, F., Jones, H . E. H., Waynforth, H . B., Brit. J. Cancer (1966) 20, 1341-144. 61. Purchase, I. F. H., van der Watt, J. J., Food Cosmet. Toxicol. (1970) 8, 289-295. 62. Hamilton, P. B., Nelson, R. R., Harris, B. S. H., Appl. Microbiol. (1968) 16, 1719-1722. 63. Binder, M., Tamm, C., Turner, W. B., Minato, H., J. Chem. Soc., Perkin Trans. 2 (1973) 1146-1147. 64. Rothweiler, W., Tamm, C., Experientia (1966) 22, 750-752. 65. Rothweiler, W., Tamm, C., Helv. Chim. Acta (1970) 53, 696-724. 66. McLaughlin, G. M., Sim, G. Α., Kiechel, T. R., Tamm, C., Chem. Commun. (1970) 1398-1399. 67. Aldridge, D. C., Armstrong, J. J., Speake, R. N . , Turner, W. B., Chem. Commun. (1967) 26-27. 68. Aldridge, D. C., Armstrong, J. J., Speake, R. N., Turner, W. B., J. Chem. Soc. C (1967) 1667-1676. 69. Imperial Chemical Industries, Ltd., Fr. Patent 1,437,461 (May 6, 1966); Chem. Abstr. (1967) 66, 9972e. 70. Aldridge, D. C., Turner, W. B., J. Chem.Soc.C (1969) 923-928. 71. Minato, H., Matsumoto, M., J. Chem. Soc. C (1970) 38-45. 72. Minato, H., Katayama, T., J. Chem. Soc. C (1970) 45-47. 73. Aldridge, D. C., Burrows, B. F., Turner, W. B., Chem. Commun. (1972) 148-149.



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74. Buchi, G., Kitaura, Y., Yuan, S. S., Wright, H. E., Clardy, J., Demain, A. L., Glinsukon, T., Hunt, N., Wogan, G. N., J. Amer. Chem. Soc. (1973) 95, 5423—5425. 75. Pendse, G. S., Experientia (1974) 30, 107-108. 76. Carter, S. B., Nature (1967) 213, 261-264. 77. Spooner, B. S., Wessels, Ν. K., Proc. Nat. Acad. Sci. (1970) 66, 360-364. 78. Snow, M. H. L., Nature (1973) 244, 513-514. 79. Thomas, D. des S., Lager, N . M., Manavathu, Ε. Κ., Can. J. Bot. (1973) 51, 2269—2273. 80. Thomas, D. des S., Lutzac, M., Manavathu, Ε. K., Nature (1974) 249, 140-142. 81. Defendi, U., Stoker, M. G. P., Nature, New Biol. (1973) 242, 24-26. 82. Kletzien, R. F., Perdue, J. F., Springer, Α., J. Biol. Chem. (1972) 247, 2964-2966. 83. Mizel, S. B., Wilson, L., J. Biol. Chem. (1972) 247, 4102-4105. 84. Thompson, R. G., Thompson, A. D., Can. J. Bot. (1973) 51, 933-936. 85. Wessels, Ν. K., Spooner, B. S., Ash, J. F., Bradley, M. O., Luduena, Μ. Α., Taylor, E. L., Wrenn, J. T., Yamada, Κ. M., Science (1971) 171, 135143. 86. Lin, S., Santi, D. V., Spudich, J. Α., J. Biol. Chem. (1974) 249, 2268-2274. RECEIVED November 8, 1974.


Mycotoxins and Other Fungal Related Food Problems

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