Xenobiotic Conjugation Chemistry - American Chemical Society

3 Xenobiotic Conjugation in Insects C. F. Wilkinson

Downloaded by CORNELL UNIV on October 30, 2016 | http://pubs.acs.org Publication Date: January 24, 1986 | doi: 10.1021/bk-1986-0299.ch003

Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, NY 14853

Insect species possess a diverse spectrum of enzymat i c conjugation capabilities that allow them to effect the secondary metabolism of a wide variety of pesticides and other xenobiotics containing appropriate hydroxyl, carboxyl or amino groups. The range of reactions catalyzed by insects includes glycoside, sulfate, and phosphate formation and a variety of conjugations involving glutathione and amino acid conjugation. A major difference between insects and mammals i s that the former u t i l i z e glucose rather than glucuronic acid in the formation of glycoside conjugates. There i s also evidence that enzymatic conjugation in insects may constitute an important mechanism for the regulation of insect steroid hormones such as the ecdysteroids. Insects, like most other living organisms, have evolved a remarkable battery of enzyme-catalyzed reactions that provides an effective biochemical defense against the potentially toxic effects of a large number of naturally occurring and synthetic chemicals (1-5). In addition to having a versatile cytochrome P-450-mediated mixedfunction oxidase system that i s responsible for the primary (phase I) metabolism of xenobiotics, insects also possess a variety of conjugation (phase II) mechanisms that catalyze the all-important final step in the conversion of lipophilic xenobiotics to polar, water-soluble, readily-excretable products (3-6). Major phase II reactions that have been demonstrated to occur in insects include xenobiotic conjugations with glycoside, sulfate, phosphate, amino acid and glutathione (3-7). With the exception of the utilization of glucose rather than glucuronic acid in glycoside formation, the conjugation reactions occurring in insects are qualitatively similar to those present in mammals and higher organisms. Unfortunately, few attempts have been made to isolate and characterize the enzymes catalyzing these reactions in insects and in many cases the sum total of the evidence indicating the 0097-6156/86/0299-0048S06.00/0 © 1986 American Chemical Society

Paulson et al.; Xenobiotic Conjugation Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

3. WILKINSON

Xenobiotic Conjugation in Insects

49

existence of a p a r t i c u l a r mechanism rests e n t i r e l y on the i s o l a t i o n of the conjugate i n the excreta or body tissues of treated insects. The following constitutes a b r i e f review of our rather woeful state o f knowledge of insect conjugation reactions and t h e i r role i n xenobiotic and intermediary metabolism.


Glycoside

formation

In i n s e c t s , as i n mammals, glycoside formation constitutes the major mechanism f o r the conjugation of xenobiotic phenols. In contrast to mammals, however, where the major sugar conjugates are 3-glucuronides, insects predominantly form the corresponding 3-glucosides (3,6,7). Since t h i s also appears to be the case f o r a l l plants and other invertebrates, 3-glucoside formation undoubtedly constitutes a more ubiquitous conjugation mechanism than the better known mammalian glucuronide system (7). Early reports that houseflies (Musca domestica) and b l o w f l i e s "Q-ucilia sericata) were capable of forming glucuronides as well as glucosides following treatment with naphthalene and a-naphthol ( 8 ) , have not been confirmed and i t i s now generally accepted that glucosides are the only sugar conjugates produced by insects (3). 0-and j>-glucosides from phenols (or alcohols) and t h i o l s , r e s p e c t i v e l y , are those most commonly i s o l a t e d from insect species although the i d e n t i f i c a t i o n of benzoylglucoside as a normal product in cockroaches (9) suggests that ester glucosides of xenobiotic acids may also be produced. To date, no N-glucosides have been i s o l a t e d from insects. By analogy with the glucuronide conjugation mechanism i n mammals (6,10), i t i s probable that uridine diphosphoglucose (UDPG) constitutes the glucosyl donor i n insects and that t r a n s f e r of glucose to an appropriate hydroxy or mercapto acceptor i s catalyzed by a UDP-glucosyltransferase (Figure 1) (3,6). UDPG i s a normal component of carbohydrate metabolism i n locust species (11) and has been detected i n silkworms (Bombyx mori) (12). Few attempts have been made to characterize insect g l u c o s y l transferases and the reports that do e x i s t are quite equivocal. Thus, i n contrast to mammalian glucosyltransferases that are l o c a l i z e d i n the microsomal f r a c t i o n of t i s s u e homogenates ( 6 ) , those from the housefly, cockroach (Periplaneta americana) and locust (Schistocerca cancel lata) are reported to be associated with the 15,000-20,OOOg p e l l e t (13,14) and that from the tobacco hornworm (Manduca Sexta) with the high speed supernatant (14). The enzyme has been i d e n t i f i e d i n gut and f a t body tissues oT~the few insect species studied and may have a f a i r l y broad t i s s u e d i s t r i bution. Judging from i t s broad d i s t r i b u t i o n among plants and invertebrates and i t s r e l a t i v e l y rare occurrence i n mammals, glucosylation appears to have evolved as a conjugation mechanism p r i o r to glucuronidation. Smith (7) speculating on why evolution might have 9


50

XENOBIOTIC CONJUGATION CHEMISTRY

favored the development of glucuronide conjugation over glucoside formation, suggested that active secretion of a c i d i c glucuronides i n the vertebrate kidney tubule or i n the b i l e might have proved advantageous i n the evolution of higher species.


Sulfate conjugation The a b i l i t y to form sulfate esters of xenobiotic phenols i s widely d i s t r i b u t e d throughout the animal kingdom (6,17,15) and along with glucoside formation appears to constitute a major conjugation mechanism i n most insect species (3,4,6,7). A f t e r studying the conjugation of m-aminophenol, 8-hydroxyquinoline and 7-hydroxycoumarin i n 15 species of insects representing f i v e d i f f e r e n t orders, Smith (16) concluded that although s u l f a t e conjugation occurred i n a l l species examined, glucoside formation remained the predominant metabolic pathway. Sulfate formation has also been demonstrated i n a variety of other invertebrates including spiders, scorpions and t i c k s ( 7 ) , although the arachnids appear to possess no a l t e r n a t i v e glycosTde mechanism f o r phenol conjugation. As a r e s u l t of i t s ubiquitous d i s t r i b u t i o n and i t s presence i n the p r i m i t i v e arthropod peripatus (Peripatoides novazealandiae), i t was suggested that s u l f a t e conjugation might constitute a p r i m i t i v e detoxication pathway that was of considerable importance p r i o r t o the evolution of glucoside formation (17). This contrasts sharply with the views of Dodgson and Rose (T8) who suggested that the metabolism of xenobiotics v i a s u l f a t e conjugation may be a r e l a t i v e l y recent evolutionary development that has become increasingly sophisticated i n higher mammals. Most studies demonstrating s u l f a t e conjugation i n insects have been l i m i t e d to the i d e n t i f i c a t i o n of conjugates excreted by insects treated i n vivo with appropriate phenols (16,17,19). Based on the few iji v i t r o studies that have been conducted, however, the insect enzyme system appears to be s i m i l a r to that found i n mammal i a n t i s s u e s (20,21), and probably follows the same three-step reaction sequence established i n mammals (Figure 2) (3,6,15). To date, however, formation of adenosine 5'-phosphosulfate (APS) and the high energy sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS) (Figure 3) have not been unequivocally established i n insect species. An active s ^ l f o t r a n s f e r a s e system requiring ATP, inorganic s u l f a t e and Mg , has been demonstrated i n the high speed (100,000g) supernatant f r a c t i o n s of tissue homogenates from eight species of insects representing four major orders (Diptera, Hymenoptera, Orthoptera and Lepidoptera) (21). Sulfotransferase a c t i v i ty was p a r t i c u l a r l y high i n preparations from the gut tissues of the southern armyworm (Spodoptera eridania) and other lepidopterous larvae and, i n addition to catalyzing the s u l f a t i o n of £-nitrophenol, the enzyme was a c t i v e towards a variety of plant, insect


WILKINSON

Xenobiotic

Conjugation

in Insects

UDPG D-glucose 1-phosphate • UTP

» UDP-«-D-glucose • P

2


pyrophoaphorylase

UDP-a-D-glucose

Figure 1.

RO-0-D-glucoside

Formation of 3-D-glucoside from xenobiotic alcohol or phenol (ROH).

ATP

A T P + S0j"^=^ A P S + P 0?~ 2

SULFURYLASE

ADENOSINE

APS

• ATP

PAPS

• ADP

5 - P H O S P H O S U L F A T E KINASE

PAPS

•

ROH

* ROSO3H

+ADP

SULFOTRANSFERASE

Figure 2. Three-step reaction sequence i n formation of s u l f a t e esters.



52


and mammalian s t e r o i d s 3 - s i t o s t e r o l (20,21).

including

cholesterol,

a-ecdysone

and

The a b i l i t y o f i n s e c t s u l f o t r a n s f e r a s e s t o c a t a l y z e the s u l f a t i o n o f p l a n t and i n s e c t s t e r o i d s may s i m p l y r e f l e c t t h e broad s u b s t r a t e s p e c i f i c i t y o f the enzymes. On the o t h e r hand, i t may be i n d i c a t i v e o f a more i m p o r t a n t p h y s i o l o g i c a l f u n c t i o n o f the enzymes. S u l f a t e e s t e r s o f c h o l e s t e r o l , campesterol and 3 - s i t o s t e r o l have been i d e n t i f i e d i n t h e meconium o f t o b a c c o homworm (M. s e x t a ) pupae ( 2 2 ) , and t h e s e s t e r o i d s a r e known p r e c u r s o r s o f aand 3-ecdysone and o t h e r m o l t i n g hormones i n t h i s s p e c i e s ( 2 3 ) . F u r t h e r , t h e r e i s e v i d e n c e t h a t h o u s e f l i e s (M. domestica) and diapausing pupae o f M. s e x t a c o n v e r t 22,25^-bi sdeoxyecdysone, a-ecdysone and 20-hydroxyecdysone i n t o s u l f a t e and glucoside conjugates (24). S i n c e i n s e c t s a r e i n c a p a b l e o f de novo s y n t h e s i s o f the s t e r o i d r i n g , the i n s e c t s t e r o i d hormones must be s y n t h e s i z e d from a v a r i e t y of phytosteroids ingested i n the d i e t (25,26). It is e n t i r e l y p o s s i b l e , t h e r e f o r e , t h a t i n s e c t s might u t i l i z e the s u l f o c o n j u g a t i o n pathway t o s t o r e p h y t o s t e r o i d s o r o t h e r p r e c u r s o r s o f a- and 3-ecdysone. F u r t h e r m o r e , by analogy w i t h the suggested r o l e o f s u l f o c o n j u g a t i o n i n mammalian s t e r o i d hormone metabolism (18) i n s e c t s may use t h i s r e a c t i o n i n c o n c e r t w i t h an a p p r o p r i a t e a r y l s u l f a t a s e t o r e g u l a t e t i t e r s o f t h e i r s t e r o i d hormones ( 1 9 , 2 0 ) . T h i s would c o n s t i t u t e a r e a d i l y r e v e r s i b l e mechanism whereby the r e q u i r e d b a l a n c e between a c t i v e ( f r e e ) and i n a c t i v e ( c o n j u g a t e d ) forms o f a- and 3-ecdysone and o t h e r e c d y s t e r o i d s c o u l d be a c h i e v e d . The p o s s i b l e e x i s t e n c e o f such a mechanism i s supported by the age-dependent changes i n s u l f o t r a n s f e r a s e and a r y l s u l f a t a s e a c t i v i t i e s observed i n t h e midgut t i s s u e s o f l a t e l a r v a l s o u t h e r n armyworm l a r v a e ( 2 7 ) . Thus, a r y l s u l f a t a s e a c t i v i t y ( p r o b a b l y of lysosomal o r i g f n ) was found t o be h i g h e s t d u r i n g the l a r v a l m o l t ( F i g u r e 4) and c o u l d r e g u l a t e the t i t e r o f f r e e e c d y s t e r o i d p r e s e n t at t h i s time. Although several s u l f o t r a n s f e r a s e s w i t h d i f f e r e n t substrate s p e c i f i c i t i e s have been i s o l a t e d from mammlian t i s s u e s , the presence o f i s o z y m i c forms has not y e t been e s t a b l i s h e d i n i n s e c t s . Phosphate c o n j u g a t i o n W h i l e t h e b i o s y n t h e s i s o f phosphate e s t e r s i s common i n i n t e r m e d i a r y m e t a b o l i s m , t h e c o n j u g a t i o n o f f o r e i g n compounds w i t h phosphate i s encountered only r a r e l y i n v e r t e b r a t e species ( 3 , 7 , 2 8 ) . Indeed, t o d a t e , i n s e c t s appear t o be the o n l y major group o f organisms t h a t u t i l i z e t h i s pathway t o any s i g n i f i c a n t e x t e n t i n the metabol i s m o f f o r e i g n compounds ( 3 , 6 , 7 ) . Phosphate c o n j u g a t e s have been i d e n t i f i e d i n t h e b o d i e s and e x c r e t a o f l a r v a e o f New Z e a l a n d g r a s s grubs ( C o s t e l y t r a z e a l a n d i c a ) , and o f a d u l t h o u s e f l i e s (M. domestica) and b l o w f l i e s ( L . s e r i c a t a ) t r e a t e d i n v i v o w i t h 1-napFithol, 2-naphthol and p - n i t r o p h e n o l ( 2 9 ) .


3.

WILKINSON

Xenobiotic

NH

Conjugation

53

in Insects

0

i

r

v

O- P-O

ROH

-»

O

•

CH

ROS03


SULFOTRANSFERASE O-P-O" II O

Adenosine 3,5-diphosphate

3-Phosphoadenosine 5-phosphosulfate (PAPS)

Figure 3. Transfer of s u l f a t e from PAPS to xenobiotic alcohol or phenol (ROH). 100

r

-glutamyl glutathione (GSH)

>-glutamyl transferase

glutamate

0

II C-OH 1 HC-CH-SR I * HN-COCH3

AcCoA

O II C-OH 1 HC-CH SR I NH

0 II C - glycine peptidase

HC-CH SR 2

2

acety lase

1 NH

2

mercapturic

2

glycine

acid

F i g u r e 6.

Mercapturic

acid

formation. •

CH -X 3

C-glycine

+

3

HX

Displacement

GSH

HC-CH SH

S -

2

I

transferase Addition -

HN->-glutamyl Glutathione

GS-CH

elimination

(GSH)

GsY0V 2 N 0

+

CI GSH RSCN Organic

+

GSH

•

RSSG

+

HCN

S-transferase

thiocyanate

F i g u r e 7.

Reactions

of

GSH-S-transferases.


H C I

3.

WILKINSON

Xenobiotic

Conjugation

in Insects

57

nates the r e a c t i o n w i t h G S H - S - t r a n s f e r a s e does not r e s u l t i n a G S H - t h i o e t h e r but i n s t e a d y i e l d s c y a n i d e and t h e corresponding mixed d i s u l f i d e , p r o b a b l y i n d i c a t i n g a t t a c k on t h e s u l f u r o f the t h i o c y a n o group.


I n s e c t G S H - S - t r a n s f e r a s e s have r e c e i v e d a good deal o f a t t e n t i o n i n r e c e n t y e a r s because o f t h e i r a b i l i t y t o c a t a l y z e the d e a l k y l a t i o n and d e a r y l a t i o n o f a wide v a r i e t y o f organophosphorus i n s e c t i c i d e s ( 3 , 6 , 4 1 ) ( F i g u r e 8) as w e l l as y - h e x a c h l o r o c y c l o h e x a n e (44). The d e t o x i c a t i o n r e a c t i o n s t h a t r e s u l t have been i m p l i c a t e d i n i n s e c t r e s i s t a n c e to these i n s e c t i c i d e s (45,46). GSH-S-transferase a c t i v i t y has been found i n a l l insect s p e c i e s examined a l t h o u g h t h e l e v e l o f a c t i v i t y v a r i e s w i t h the s p e c i e s and s t r a i n o f i n s e c t and w i t h t h e s u b s t r a t e employed (3,6,41). I t i s e v i d e n t t h a t , as i n mammals, t h e i n s e c t enzymes a r e p r e s e n t as a group o f s t r u c t u r a l l y s i m i l a r isozymes w i t h v a r y i n g degrees o f o v e r l a p p i n g s u b s t r a t e s p e c i f i c i t y ; the enzymes o c c u r i n the 100,000g s u p e r n a t a n t s o f a v a r i e t y o f i n s e c t t i s s u e s . Enzyme p u r i f i c a t i o n s t u d i e s i n d i c a t e t h a t a l l GSH-S-transferases have a s i m i l a r m o l e c u l a r w e i g h t ( ~ 5 0 , 0 0 0 ) and c o n s i s t o f two a p p r o x i m a t e l y equal s u b u n i t s ( 4 0 ) . During t h e l a s t two decades t h e r e has been c o n t i n u i n g c o n t r o v e r s y c o n c e r n i n g t h e c l a s s i f i c a t i o n o f the enzyme DDT-dehydroc h l o r i n a s e as a G S H - S - t r a n s f e r a s e (6). DDT-dehydrochlorinase is the enzyme t h a t c o n v e r t s DDT t o the r e l a t i v e l y n o n - t o x i c DDE and has been i n t e n s i v e l y s t u d i e d i n h o u s e f l i e s and o t h e r insects because o f i t s e s t a b l i s h e d importance i n i n s e c t r e s i s t a n c e t o DDT. DDT d e h y d r o c h l o r i n a s e has been h i g h l y p u r i f i e d from D D T - r e s i s tant houseflies (47) and has been c h a r a c t e r i z e d as a s o l u b l e l i p o p r o t e i n w i t h a m o l e c u l a r w e i g h t o f about 120,000 and c o n s i s t i n g o f f o u r equal s u b u n i t s . Formation o f the t e t r a m e r r e p o r t e d l y o c c u r s o n l y i n t h e presence o f DDT, and GSH i s r e q u i r e d f o r d e h y d r o c h l o r i n a t i o n (48). In c o n t r a s t t o most G S H - S - t r a n s f e r a s e s t h e r e i s no e v i d e n c e f o r the f o r m a t i o n o f a DDT-GSH adduct and no e v i d e n c e t h a t GSH i s d e p l e t e d d u r i n g t h e course o f t h e r e a c t i o n . More r e c e n t l y DDT-dehydrochlorinase has been i s o l a t e d and p u r i f i e d ( ^ 6 6 0 - f o l d ) t o apparent homogeneity from h o u s e f l i e s ( 4 9 ) . In c o n t r a s t t o t h a t d e s c r i b e d i n e a r l i e r s t u d i e s , t h i s enzyme was found t o be a dimer w i t h s u b u n i t s o f m o l e c u l a r w e i g h t s o f 23,000 and 25,000. I t was a l s o found t o possess s u b s t a n t i a l G S H - S - t r a n s f e r a s e a c t i v i t y towards 2 , 4 - d i n i t r o c h l o r o b e n z e n e and 3 , 4 - d i c h l o r o nitrobenzene. Based on i t s s t r u c t u r e , c a t a l y t i c a c t i v i t y and chromatographic b e h a v i o r i t was c o n c l u d e d t h a t t h e p u r i f i e d h e t e r o d i m e r i c DDT-dehydrochlorinase was indeed a GSH-S-transferase isozyme ( 4 9 ) . I t was proposed t h a t i n s t e a d o f t h e n u c l e o p h i l i c substitution usually observed in GSH-S-transferase activity, D D T - d e h y d r o c h l o r i n a t i o n by t h i s enzyme i n v o l v e s an E2 e l i m i n a t i o n r e a c t i o n i n which the GS" t h i o l a t e a n i o n a b s t r a c t s t h e hydrogen on t h e C-2 o f DDT and t h i s i n i t i a t e s t h e d e p a r t u r e o f the c h l o r i n e atom from C - l (49) ( F i g u r e 9 ) .


58


R (

V

RO /

X

GSH

\ O-Y ~ S

R

T R A N S F E R A S E

° v

H O '

X

x

O - Y

DEALKYLATION

Where.

R O

R-ALKYL

N

^ X

X » S or O

RO^


V «ARYL

X

O H

OEARYLATION

F i g u r e 8.

GSH-S-transferase a c t i v i t y insecticides.

GSH S-TRANSFERASE

Nucleophilic substitution

towards

organophosphorus

DDT DEHYDROCHLORINASE

E

2

«

l i m l n a t i o n

1. Abstraction off benzylic hydrogen 2. Elimination chlorine F i g u r e 9.

(C-2)

(C-1)

Proposed mechanisms o f G S H - S - t r a n s f e r a s e 2 , 4 - d i n i t r o c h l o r o b e n z e n e and DDT.

towards


3.

WILKINSON

Xenobiotic

Conjugation

in Insects

59

It i s , of course, entirely possible that the DDT-dehydrochlorinases purified by Dinamarca's group (47) and by Clark (49) are d i s t i n c t enzyme proteins since they apparently d i f f e r in several respects. Of particular interest in the case of the former i s that, in the absence of DDT, the enzyme catalyzes the oxidation of GSH to the corresponding glutathione disulfide GSSH. Although the mechanism of GSH oxidation has not been established, i t is of interest that GSH-S-transferases having peroxidase a c t i v i t y have been reported where i t is apparent that GSH i s attacking an elect r o p h i l i c oxygen (50).


Summary It should be clear from the foregoing discussion that our current state of knowledge concerning the mechanisms of xenobiotic conjugation in insects leaves much to be desired. To date, studies on xenobiotic metabolism in insect species have been focused mainly on the pathways of primary metabolism and have been stimulated by the importance of such pathways in insect resistance to insecticide chemicals. Conjugation reactions are not considered to be rate limiting in insecticide metabolism and consequently have been largely neglected. However, i t is now becoming increasingly apparent that conjugation reactions may play an important physiological role in the regulation of insect ecdysteroids. Perhaps this p o s s i b i l i t y w i l l provide the necessary stimulus for more comprehensive studies in the future. Literature cited 1.

Wilkinson, C. F. In "Foreign Compound Metabolism"; Caldwell, J.; Paulson, G. D., Eds.; Taylor and Francis: London, 1984; pp. 133-147. 2. Brattsten, L. B. In "Herbivores: Their Interactions with Secondary Plant Metabolites"; Rosenthal, A.; Janzen, D. H., Eds.; Academic: New York, 1979; pp. 199-270. 3. Dauterman, W. C.; Hodgson, E. In "Biochemistry of Insects"; Rockstein, M., Ed.; Academic: New York, 1978; Chap. 13. 4. Smith, J. N. In "Comparative Biochemistry"; Florkin, M.; Mason, H. S., Eds.; Academic: New York, 1964; Vol. VI, pp. 403-448. 5. Wilkinson, C. F. and Brattsten, L. B. Drug Metab. Revs. 1972, 1, 153-228. 6. Yang, R. S. H. In "Insecticide Biochemistry and Physiology"; Wilkinson, C. F., Ed.; Plenum: New York. 1976; Chap. 5. 7. Smith, J. N. Advan. Comp. Physiol. Biochem. 1968, 3, 173-232. 8. Terriere, L. C.; Boose, R. B.; Roubal, W. T. Biochem. J . 1961, 79, 620-623. 9. Quilico, A.; P i o z z i , F.; Pavan, M.; Mantica, E. Tetrahedron Lett. 1959, 5, 10-14. 10. "Kasper, C. B.; Henton, D. In "Enzymatic Basis of Detoxicat i o n " ; Jacoby, W. B., Ed.,; Academic: New York, 1980; Chap. 1.



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