Biological Actions and Metabolic Transformations of Furanocoumarins

Chapter 15

Biological Actions and Metabolic Transformations of Furanocoumarins Downloaded by NANYANG TECHNOLOGICAL UNIV on September 18, 2017 | http://pubs.acs.org Publication Date: May 7, 1987 | doi: 10.1021/bk-1987-0339.ch015

G. Wayne Ivie Agricultural Research Service, U.S. Department of Agriculture, College Station, TX 77841

Furanocoumarins are a group of potent photosensitizing molecules that occur as secondary constituents of a large number of plant families. Furanocoumarins have important uses in human medicine, are potent phototoxins to both man and domestic animals, are important host resistance mediators i n a number of plant species, and exhibit t o x i c i t y against a wide range of organisms. Furanocoumarin b i o l o g i c a l actions are expressed most potently upon activation by long wavelength u l t r a v i o l e t l i g h t , but these compounds also have l i g h t Independent actions--by mechanisms that are at present not understood. In mammals, birds, and insects, furanocoumarins are often rapidly metabolized and excreted, and i n insects, the rate of metabolism i s the major determinant of r e l a t i v e tolerance to these compounds in the d i e t . Metabolic mechanism i n animals include O-alkyl hydrolysis, hydrolysis of the pyrone ring, and oxidative opening of the furan ring, i n addition to other oxidative, reductive, and conjugative reactions.

Furanocoumarins o c c u r n a t u r a l l y as secondary m e t a b o l i t e s i n h i g h e r p l a n t s (J_). These compounds have been i s o l a t e d f r o m w e l l over a hundred p l a n t s p e c i e s r e p r e s e n t i n g a t l e a s t e i g h t f a m i l i e s , a l t h o u g h the U m b e l l i f e r a e and Rutaceae appear to have, In p a r t i c u l a r , l a r g e numbers of s p e c i e s t h a t c o n t a i n furanocoumarins ( 2 ) . S p e c i f i c furanocoumarin d e r i v a t i v e s g e n e r a l l y a r i s e i n n a t u r e from two c o n f i g u r a t i o n s of the b a s i c t r i c y c l i c r i n g s t r u c t u r e ( F i g u r e 1 ) . The number of d i s t i n c t f u r a n o c o u m a r i n s t r u c t u r e s p r e s e n t l y known from p l a n t s i s q u i t e l a r g e — w e l l over 200 d i f f e r e n t furanocoumarin s t r u c t u r e s have thus f a r been i d e n t i f i e d ( 3 ) . Most i n d i v i d u a l furanocoumarins are d i s t i n g u i s h e d by a l k o x y or a l k y l s u b s t i t u t i o n at e i t h e r of the two a v a i l a b l e a r o m a t i c p o s i t i o n s , a t the a v a i l a b l e carbons of the f u r a n r i n g o r , much l e s s p r e d o m i n a n t l y , This chapter not subject to U.S. copyright Published 1987 American Chemical Society

Heitz and Downum; Light-Activated Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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F i g u r e 1. S t r u c t u r e s i n d i c a t i n g the r i n g f u s i o n o f l i n e a r furanocoumarins ( P s o r a l e n ) and a n g u l a r furanocoumarins (Isopsoralen).


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the pyrone r i n g . Many n a t u r a l l y - o c c u r r i n g furanocoumarins e x h i b i t s a t u r a t i o n of the f u r a n o l e f i n l c m o i e t y . M o n o s u b s t l t u t e d and d i s u b s t i t u t e d furanocoumarins are common, but t r i - or g r e a t e r s u b s t i t u t i o n i s r a r e . The pathways i n v o l v e d i n the b i o s y n t h e s i s of furanocoumarins have been t h o r o u g h l y s t u d i e d and are a t p r e s e n t q u i t e w e l l understood (4-6).


Mode of B i o l o g i c a l A c t i o n s L i g h t Dependent A c t i o n s . Furanocoumarins are of i n t e r e s t from a g r i c u l t u r a l , m e d i c i n a l , p u b l i c h e a l t h , and e n v i r o n m e n t a l v i e w p o i n t s because they are h i g h l y p h o t o b i o l o g l c a l l y a c t i v e . Wavelengths i n the near u l t r a v i o l e t (320-360 nm) are the most e f f e c t i v e a c t i v a t i n g w a v e l e n g t h s , even though furanocoumarins absorb r e l a t i v e l y p o o r l y i n this region (7J. I t i s g e n e r a l l y a c c e p t e d t h a t the p h o t o b i o l o g i c a l a c t i o n s of furanocoumarins r e s u l t , i n at l e a s t major p a r t , from t h e i r i n t e r c a l a t i o n I n t o the double h e l i x of DNA where, upon l i g h t a c t i v a t i o n , they form c y c l o b u t a n e adducts w i t h p y r i m i d i n e bases ( 8 ) . Both the f u r a n and pyrone r i n g double bonds are p o t e n t i a l a l k y l a t i n g m o i e t i e s ; the l i n e a r furanocoumarins ( p s o r a l e n s ) are known t o form b o t h mono- and d i a d d u c t s ( c r o s s l i n k s ) , whereas the a n g u l a r c o n f i g u r a t i o n of the i s o p s o r a l e n s p e r m i t s o n l y monoadduction (8^). A l t h o u g h DNA p h o t o a l k y l a t i o n i s a w e l l - d e f i n e d m o l e c u l a r event a s s o c i a t e d w i t h furanocoumarin i n t e r a c t i o n s w i t h l i v i n g m a t t e r , r e c e n t s t u d i e s have produced evidence t h a t furanocoumarins b i n d w i t h s p e c i f i c , s a t u r a b l e , h i g h a f f i n i t y s i t e s on or i n mammalian c e l l s and t h a t such b i n d i n g i s to some e x t e n t i r r e v e r s i b l e upon UV exposure ( 9 ) . I t was proposed t h a t s p e c i f i c r e c e p t o r b i n d i n g phenomena as modes of a c t i o n , r a t h e r than s i m p l y the a l k y l a t i o n of DNA, might be more c o n s i s t e n t w i t h the known d i v e r s i t y of furanocoumarin b i o l o g i c a l a c t i o n s ( 9 ) . L i g h t - I n d e p e n d e n t A c t i o n s . A l t h o u g h furanocoumarins are known p r i m a r i l y f o r t h e i r l i g h t - c a t a l y z e d r e a c t i o n s , they n e v e r t h e l e s s have demonstrated b i o l o g i c a l a c t i v i t i e s i n the absence of a c t i v a t i n g r a d i a t i o n . Furanocoumarins are moderately t o x i c to l a b o r a t o r y mammals i n the dark, from both acute and subacute s t a n d p o i n t s ( 8 , 1 0 ) . Furanocoumarins are a l s o somewhat t o x i c to c e r t a i n i n s e c t s i n the d a r k , but such may r e s u l t from a n t i f e e d a n t a c t i v i t y more so than i n h e r e n t t o x i c i t y per se ( 1 1 ) . Some furanocoumarins are weakly mutagenic i n the absence of l i g h t , by thus f a r u n e x p l a i n e d mechanisms (12-16). C e r t a i n of the e n v i r o n m e n t a l e f f e c t s of furanocoumarins ( v i d e i n f r a ) are c l e a r l y l i g h t Independent b u t , a g a i n , the mechanisms i n v o l v e d are not known. R o l e o f Oxygen i n Furanocoumarin A c t i o n . In the p h o t o a d d u c t i o n of furanocoumarins w i t h DNA, t h e r e i s c l e a r l y no d i r e c t involvement of oxygen. However, the p h o t o g e n e r a t i o n of s i n g l e t oxygen by furanocoumarins has been w e l l documented, and such r e a c t i o n s may p o t e n t i a l l y be r e s p o n s i b l e f o r d i r e c t enzyme i n a c t i v a t i o n and membrane d i s r u p t i o n ( 1 7 ) . M o n o f u n c t i o n a l ( a n g u l a r ) furanocoumarins appear to be more e f f i c i e n t g e n e r a t o r s of s i n g l e t oxygen than a r e l i n e a r furanocoumarins ( 1 7 ) . They a l s o appear t o be more p h o t o c a r c i n o g e n i c than the b i f u n c t i o n a l ( l i n e a r ) f u r a n o c o u m a r i n s ,



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and i t has been suggested t h a t a c t i v a t e d oxygen may p l a y a major r o l e i n the p h o t o c a r c i n o g e n l c i t y of these compounds ( 2 ) . Other s t u d i e s , however, have shown t h a t s i n g l e t oxygen g e n e r a t i o n i s not s i g n i f i c a n t l y c o r r e l a t e d w i t h the g e n o t o x i c i t y of e i t h e r l i n e a r o r a n g u l a r f u r a n o c o u m a r i n s , u s i n g an e x c i s i o n r e p a i r d e f i c i e n t s t r a i n of IS. c o l i as the t e s t organism ( 1 8 ) . S i m i l a r l y , n e i t h e r s i n g l e t oxygen (19) n o r s u p e r o x i d e r a d i c a l (20) f o r m a t i o n c o u l d be c o r r e l a t e d w i t h s k i n p h o t o s e n s i t i z i n g a c t i v i t y amongst a c o n s i d e r a b l e a r r a y of l i n e a r and a n g u l a r furanocoumarins. Structure-Activity Considerations A v a i l a b l e d a t a on the s k i n p h o t o s e n s i t i z i n g a c t i v i t y of furanocoumarins i n d i c a t e t h a t , g e n e r a l l y , l i n e a r furanocoumarins a r e more b i o l o g i c a l l y a c t i v e than the a n g u l a r analogs ( 8 ) . Recent s t u d i e s have, however, p r o v i d e d d a t a to suggest t h a t under n a t u r a l c o n d i t i o n s of m u I t i w a v e l e n g t h l i g h t a c t i v a t i o n , the i n h e r e n t b i o l o g i c a l a c t i v i t i e s of comparable l i n e a r and a n g u l a r furanocoumarins may not be a p p r e c i a b l y d i f f e r e n t ( 2 1 ) . I t i s a l s o g e n e r a l l y h e l d t h a t p h o t o s e n s i t i z i n g a c t i v i t y decreases w i t h i n c r e a s i n g c h e m i c a l c o m p l e x i t y of the a l k y l or a l k o x y s u b s t l t u e n t ( 8 ) , but some s t u d i e s have shown t h a t some of the more c h e m i c a l l y complex (and more p o l a r ) furanocoumarins are h i g h l y p h o t o t o x i c when the s k i n , a b a r r i e r t o a b s o r p t i o n , i s bypassed ( 2 2 ) . A r y l h y d r o x y l a t e d f u r a n o c o u m a r i n s , s e v e r a l of which occur i n n a t u r e , a r e i n a c t i v e as s k i n p h o t o s e n s i t i z e r s ( 8 ) . S t r u c t u r e - a c t i v i t y c o r r e l a t i o n s f o r furanocoumarins w i t h r e s p e c t t o b i o l o g i c a l a c t i o n s o t h e r than s k i n p h o t o s e n s i t i z a t i o n are e i t h e r i n c o m p l e t e or lacking. T o x i c o l o g i c a l and Other B i o c h e m i c a l E f f e c t s Because furanocoumarins are p o t e n t DNA p h o t o a l k y l a t l n g a g e n t s , I t i s not s u r p r i s i n g t h a t they show c o n s i d e r a b l e p h o t o t o x i c i t y toward a wide v a r i e t y of l i f e forms. Upon l i g h t a c t i v a t i o n , furanocoumarins are p o w e r f u l a n t i m i c r o b i a l agents ( 8 , 2 3 ) , nematocides ( 2 4 ) , i n s e c t i c i d e s ( 2 5 , 2 6 ) , o v i c i d e s ( 2 7 ) , and p o w e r f u l s k i n p h o t o s e n s i t i z e r s a g a i n s t man (8) and a n i m a l s ( 2 8 ) . They are a l s o possibly h e r b i c i d a l (29). Furanocoumarins are m o l l u s c i c i d a l (30,31) and p i s c i c i d a l ( 8 ) , but the r o l e of l i g h t i n these e f f e c t s i s u n c l e a r . C o n s i d e r i n g the known m o l e c u l a r events a s s o c i a t e d w i t h the l i g h t - s e n s i t i z e d i n t e r a c t i o n of furanocoumarins w i t h l i v i n g m a t t e r , i t seems almost c e r t a i n t h a t furanocoumarins I n the presence of a c t i v a t i n g l i g h t would be p o t e n t i a l l y p h o t o t o x i c to almost any form of l i f e . In a d d i t i o n t o acute p h o t o t o x i c o l o g i c a l e f f e c t s , furanocoumarins are h i g h l y photomutagenic and a r e , i n f a c t , mammalian p h o t o c a r c i n o g e n s ( 3 2 - 3 4 ) . Furanocoumarins are known to have v a r i o u s l i g h t independent e f f e c t s on some mammalian and I n s e c t enzyme systems. The l i n e a r f u r a n o c o u m a r i n , x a n t h o t o x i n (8-methoxypsoralen) induced mouse and/or r a t a r y l hydrocarbon h y d r o x l y a s e ( 3 5 , 3 6 ) , e t h y l morphone N-demethylase ( 3 6 ) , p - n i t r o a n i s o l e - O - d e m e t h y l a s e (35) and 7-ethoxycoumarin-O-deethylase ( 3 7 ) ; i t a l s o shortened h e x o b a r b i t a l s l e e p i n g time ( 3 8 ) , and i t may i n c r e a s e l e v e l s of cytochrome P-450


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(36) a l t h o u g h t h e r e are c o n f l i c t i n g data ( 3 7 ) . X a n t h o t o x i n d i d not induce a n i l i n e h y d r o x y l a s e ( 3 6 ) . I n t e r e s t i n g l y , p s o r a l e n , i s o p s o r a l e n , and 4 , 5 * , 8 - t r i m e t h y l p s o r a l e n a t e q u i v a l e n t doses f a i l e d to e x h i b i t any enzyme i n d u c t i o n p o t e n t i a l (35,36). I n the f a l l armyworm (Spodoptera f r u g i p e r d a ) d i e t a r y x a n t h o t o x i n induced midgut g l u t a t h i o n e ^ - t r a n s f e r a s e and h e p t a c h l o r e p o x l d a s e , i n c r e a s e d cytochrome P-450 c o n t e n t , b u t i n h i b i t e d a l d r i n e p o x i d a s e , b i p h e n y l - 4 - h y d r o x y l a s e , and p - c h l o r o - N - m e t h y l a n i l i n e N-demethylase (39). Environmental I n t e r a c t i o n s On the b a s i s of r e s e a r c h o b s e r v a t i o n s t o date, the most p l a u s i b l e e x p l a n a t i o n f o r the o c c u r r e n c e o f furanocoumarins i n h i g h e r p l a n t s i s t h a t these compounds e v o l v e d as defense chemicals a g a i n s t p l a n t pathogens and h e r b i v o r e s , and as a l l e l o p a t h l c agents t o enhance c o m p e t i t i v e n e s s amongst o t h e r p l a n t s p e c i e s . Furanocoumarins i n h i b i t seed g e r m i n a t i o n (40) and p l a n t growth ( 4 1 ) — a c t i v i t i e s t h a t are almost c e r t a i n l y l i g h t - i n d e p e n d e n t because o f t h e i r e x p r e s s i o n i n the s o i l environment. The avoidance of a u t o t o x i c i t y i s a p p a r e n t l y a c c o m p l i s h e d , a t l e a s t I n p a r t , through l o c a l i z a t i o n and/or s e q u e s t r a t i o n phenomena ( 4 0 ) . Furanocoumarins are w e l l e s t a b l i s h e d as p h y t o a l e x l n s . The i n f e c t i o n of both c e l e r y and p a r s n i p w i t h c e r t a i n p a t h o g e n i c organisms r e s u l t s i n g r e a t l y enhanced b i o s y n t h e s i s and a c c u m u l a t i o n of these compounds ( 4 2 ) ; enhanced b i o s y n t h e s i s of furanocoumarins i s a l s o e l i c i t e d by a number of o t h e r s t i m u l i as w e l l ( 4 3 ) . The a n t i f e e d a n t p r o p e r t i e s o f furanocoumarins are w e l l e s t a b l i s h e d f o r a number of i n s e c t s , i n c l u d i n g s e v e r a l Spodoptera s p e c i e s (25,44-46), Mythimna u n l p u n c t a t a ( 4 7 ) , and L e p t i n o t a r s a d e c e m l i n e a t a ( 4 7 ) . C o n v e r s e l y , i n s e c t s t h a t are adapted t o feed on furanocoumarin-containing p l a n t s may p e r c e i v e these compounds as o v i p o s i t i o n s t i m u l a n t s ( 4 8 ) , and i n a t l e a s t one i n s e c t , the b l a c k s w a l l o w t a i l b u t t e r f l y , ( P a p i l i o p o l y x e n e s ) , d i e t a r y furanocoumarins a c t u a l l y enhance c a t e r p i l l a r growth r a t e and w e i g h t g a i n , perhaps by a c t i n g as f e e d i n g s t i m u l a n t s ( 4 9 ) . Furanocoumarins i n p l a n t s pose c l e a r and documented hazards t o g r a z i n g mammals. P h o t o s e n s i t l z a t l o n of domestic c a t t l e , sheep, and p o u l t r y by d i e t a r y furanocoumarins has been documented ( 2 8 ) , and there are numerous i n s t a n c e s of p h o t o s e n s i t l z a t l o n i n man a s s o c i a t e d w i t h dermal p l a n t exposures ( 8 ) . The impact of furanocoumarins on mammalian and a v i a n w i l d l i f e s p e c i e s i s e s s e n t i a l l y unknown, but i t i s l i k e l y t h a t most w i l d l i f e s p e c i e s have adapted through e v o l u t i o n a r y p r e s s u r e s t o a v o i d such p l a n t s . E v i d e n c e has r e c e n t l y been o b t a i n e d t h a t furanocoumarins are p r o b a b l y a n t i f e e d a n t s toward at l e a s t one mammalian h e r b i v o r e , the h y r a x ( P r o c a v l a c a p e n s l s ) (50). M e d i c i n a l Uses The v a r i o u s p h o t o b l o l o g l c a l a c t i o n s e x h i b i t e d by furanocoumarins a r e such t h a t these compounds have an astounding range of a c t u a l and p o t e n t i a l uses i n human m e d i c i n e . P l a n t p r e p a r a t i o n s t h a t c o n t a i n f u r a n o c o u m a r i n s , p l u s s u n l i g h t , have been used f o r thousands o f y e a r s i n the treatment o f v i t i l i g o ( 8 ) , and x a n t h o t o x i n p l u s UV


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l i g h t (PUVA t h e r a p y ) i s now the treatment of c h o i c e f o r severe p s o r i a s i s (32,33), Other human d i s o r d e r s f o r which furanocoumarins ( u s u a l l y x a n t h o t o x i n ) p l u s l i g h t have shown p o t e n t i a l l y b e n e f i c i a l e f f e c t s I n c l u d e mycosis f u n g o i d e s ( 5 1 ) , scleromyxoedma ( 5 2 ) , u r t i c a r i a pigmentosa ( 5 3 , 5 4 ) , f o l l i c u l a r mucinosis ( 5 5 ) , p a r a p s o r i a s i s ( 5 6 ) , p a l m o p l a n t a r p u s t u l o s i s ( 5 7 ) , lymphomatold p a p u l o s i s ( 5 8 ) , l i c h e n planus ( 5 9 ) , a t o p i c d e r m a t i t i s ( 6 0 ) , c e r t a i n p a r a s i t i c f u n g i ( 6 1 ) , and even herpes s i m p l e x ( 6 2 ) , a l o p e c i a a r e a t a (63,64), and leukemic cutaneous T c e l l lymphoma ( 6 5 ) . Metabolic

Transformations

Mammals. The e x t e n s i v e I n t e r e s t i n l i n e a r furanocoumarins as m e d i c i n a l agents and t h e i r impact as l i v e s t o c k and p o u l t r y p h o t o t o x i n s has l e d t o c o n s i d e r a b l e s c i e n t i f i c e f f o r t s aimed a t e l u c i d a t i n g the k i n e t i c s , b i o t r a n s f o r m a t i o n and d i s p o s i t i o n of these c h e m i c a l s i n mammalian s p e c i e s , I n c l u d i n g man. Most such e f f o r t s have been t a r g e t e d on x a n t h o t o x i n , because i t i s the furanocoumarin of c h o i c e i n most m e d i c i n a l a p p l i c a t i o n s , i s perhaps the most commonly-occurring furanocoumarin i n n a t u r e , and i s h i g h l y p h o t o b i o l o g i c a l l y a c t i v e . However, l i m i t e d b i o l o g i c a l t r a n s f o r m a t i o n s t u d i e s have a l s o been done w i t h bergapten ( 5 - m e t h o x y p s o r a l e n ) , and w i t h 4 , 5 , 8 - t r i m e t h y l p s o r a l e n w h i c h i s c l i n i c a l l y u s e f u l i n the treatment o f v i t i l i g o . The I n v i v o and i n v i t r o metabolism of x a n t h o t o x i n i n l a b o r a t o r y r a t s and mice has been the s u b j e c t of s e v e r a l s t u d i e s (66-70). I n r o d e n t s , x a n t h o t o x i n i s m e t a b o l i z e d by 1) O-demethylation; 2) a r y l h y d r o x y l a t i o n a t p o s i t i o n 5; 3) o x i d a t i o n of t h e 5,8-dihydroquinone t o the qulnone; 4) h y d r o l y s i s of the pyrone r i n g ; 5) o x i d a t i v e opening of the f u r a n r i n g ; and 6) s u l f a t e and g l u c u r o n l d e c o n j u g a t i o n ( F i g u r e 2 ) . I n v i t r o s t u d i e s have demonstrated t h a t x a n t h o t o x i n metabolism I n r a t s i s induced by p h e n o b a r b i t a l and by B-naphthoflavone ( 7 0 ) . I n r a t s , t h e r e i s some i n d i c a t i o n t h a t cleavage of the a r o m a t i c r i n g o f x a n t h o t o x i n o c c u r s to a very l i m i t e d extent (69). As i n d i c a t e d i n F i g u r e 2, x a n t h o t o x i n metabolism I n the dog ( 7 1 ) , i n the goat ( 7 2 ) , and i n man (67,73-75) f o l l o w s a t l e a s t some of t h e same pathways. I n t h e goat, a n o v e l m e t a b o l i t e r e s u l t s from s a t u r a t i o n of the pyrone r i n g p r i o r o r subsequent t o pyrone r i n g h y d r o l y s i s . A l t h o u g h not e s t a b l i s h e d e x p e r i m e n t a l l y , t h i s m e t a b o l i t e may a r i s e through r e d u c t i v e mechanisms p r e s e n t i n t h e rumen p r i o r t o a b s o r p t i o n ( 7 2 ) . D e f i n i t i v e m e t a b o l i c f a t e s t u d i e s have not been undertaken w i t h b e r g a p t e n , but a s i n g l e study o f l i m i t e d scope has p r o v i d e d good e v i d e n c e t h a t , i n man, t h e pyrone r i n g of bergapten i s h y d r o l y z e d and s u b s e q u e n t l y c o n j u g a t e d w i t h g l u c u r o n i c a c i d o r s u l f a t e p r i o r t o e x c r e t i o n i n the urine (76). S t u d i e s w i t h 4 , 5 ' , 8 - t r i m e t h y l p s o r a l e n i n mouse and man have shown t h a t the 5 - m e t h y l group i s h y d r o x y l a t e d , then o x i d i z e d t o a 5'-carboxy d e r i v a t i v e ( F i g u r e 3) (77,78). Products of f u r a n o r pyrone r i n g cleavage r e a c t i o n s were not d e t e c t e d . f

1

B i r d s . There a r e no p u b l i s h e d data on the f a t e of furanocoumarins i n any a v i a n s p e c i e s , but s t u d i e s i n p r o g r e s s i n our l a b o r a t o r i e s have shown t h a t x a n t h o t o x i n i s e x t e n s i v e l y m e t a b o l i z e d by l a y i n g



F i g u r e 2. I d e n t i f i e d m e t a b o l i c pathways f o r x a n t h o t o x i n (8-methoxypsoralen) i n r o d e n t s , humans, dogs, g o a t s , c h i c k e n s , and i n s e c t s . B r a c k e t e d compounds have not been i s o l a t e d , but a r e p o s s i b l e i n t e r m e d i a t e s i n pathways l e a d i n g t o the i d e n t i f i e d metabolites.

rat


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224 LIGHT-ACTIVATED PESTICIDES


15.

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IVIE

225


hens ( P a n g i l i n a n , N. C.; I v i e , G. W.; u n p u b l i s h e d d a t a ) . The h y d r o l y s i s of t h e O-methyl group o f x a n t h o t o x i n ( t o x a n t h o t o x o l ) o c c u r s t o a t l e a s t a l i m i t e d e x t e n t i n the hen, and p r e l i m i n a r y i n d i c a t i o n s a r e t h a t the major m e t a b o l i t e s a r i s e through f u r a n and/or pyrone r i n g cleavage r e a c t i o n s . I n s e c t s . A number of s t u d i e s have i n v e s t i g a t e d the d i s p o s i t i o n o f furanocoumarins i n i n s e c t s , w i t h the primary emphasis on e s t a b l i s h i n g how f u r a n o c o u m a r i n - t o l e r a n t s p e c i e s a v o i d p h o t o t o x i c i t y . Under c o n d i t i o n s of l a b o r a t o r y f e e d i n g of xanthotoxin t o aphids (Aphis h e r a c l e l l a o r C a v a r l e l l a pastinacae) c o n t i n u o u s l y exposed t o UV l i g h t , no p h o t o t o x i c e f f e c t was seen. No x a n t h o t o x i n m e t a b o l i t e s per se were d e t e c t e d i n e x t r a c t s of t r e a t e d a p h i d s , b u t x a n t h o t o x i n c o u l d be l i b e r a t e d by a c i d h y d r o l y s i s procedures ( 2 9 ) . I t may be t h a t aphids d e t o x i f y x a n t h o t o x i n by h y d r o l y s i s of the l a c t o n e f o l l o w e d by c o n j u g a t i o n (perhaps as a g l y c o s i d e ) . A c i d h y d r o l y s i s c o u l d y i e l d the f r e e hydroxy a c i d w h i c h then would l i k e l y l a c t o n i z e back t o x a n t h o t o x i n . The l a r v a l form of a l e a f mining d i p t e r a n , Phytomyza s p o n d y l l l , feeds on p l a n t s r i c h i n furanocoumarins and has been shown t o r a p i d l y d e t o x i f y xanthotoxin to non-photoactive m e t a b o l i t e s , a l t h o u g h the c h e m i c a l n a t u r e of these p r o d u c t s has not been i n v e s t i g a t e d (79). C a t e r p i l l a r s of the b l a c k s w a l l o w t a i l b u t t e r f l y , P a p i l i o p o l y x e n e s , a r e w e l l adapted t o feed on l i n e a r furanocoumarin rich h o s t p l a n t s , and i t i s now known t h a t t h i s i n s e c t r a p i d l y d e t o x i f i e s l i n e a r furanocoumarins ( p s o r a l e n , x a n t h o t o x i n ) as the mechanism o f t o x i c i t y avoidance (80,81^). O x i d a t i v e cleavage of the f u r a n r i n g i s the major r o u t e o f d e t o x i f i c a t i o n by P. polyxenes ( F i g u r e 2 ) ; O - d e m e t h y l a t i o n , pyrone r i n g h y d r o l y s i s , o r o t h e r pathways a r e e i t h e r n o n - e x i s t e n t o r minor. Larvae of the furanocoumarin s e n s i t i v e f a l l arrayworm (Spodoptera f r u g i p e r d a ) m e t a b o l i z e l i n e a r furanocoumarins by i d e n t i c a l pathways, y e t a t such a slow r a t e t h a t t o x i c i t y ensues (80,81). polyxenes appears t o be r e l a t i v e l y l e s s t o l e r a n t t o a n g u l a r furanocoumarins (82) and, i n d e e d , an a n g u l a r furanocoumarin ( i s o p s o r a l e n ) was m e t a b o l i z e d a t a slower r a t e than was p s o r a l e n (83). T h i s o b s e r v a t i o n may a t l e a s t p a r t l y e x p l a i n why ]>. polyxenes g e n e r a l l y a v o i d s p l a n t s t h a t c o n t a i n a p p r e c i a b l e l e v e l s of the a n g u l a r compounds. The m e t a b o l i c d e t o x i f i c a t i o n of furanocoumarins i n l e p l d o p t e r a n l a r v a e r e s u l t s , at l e a s t I n p a r t , from the a c t i o n s o f microsomal o x i d a s e s . T h i s c o n c l u s i o n i s based on d i r e c t s t u d i e s w i t h x a n t h o t o x i n and midgut or body microsomes from P. polyxenes and S. f r u g i p e r d a ( 8 4 ) , and upon o b s e r v a t i o n s t h a t the t o x i c i t y ( i n the d a r k ) o f x a n t h o t o x i n t o the corn earworm, H e l l o t h l s z e a , i s enhanced by m y r i s t i c i n and p i p e r o n y l b u t o x i d e , potent methylenedioxyphenyl I n h i b i t o r s o f microsomal o x i d a s e enzymes (11)* Metabolism

Versus E x p r e s s i o n o f B i o l o g i c a l E f f e c t s

Given the f a c t t h a t furanocoumarins r e a d i l y p h o t o a l k y l a t e DNA, these compounds can be c o n s i d e r e d as n o n s p e c i f i c p h o t o s e n s i t i z e r s capable of i n t e r a c t i n g w i t h e s s e n t i a l l y any form of l i f e under a p p r o p r i a t e l i g h t a c t i v a t i o n s c e n a r i o s . I n s i n g l e c e l l e d organisms, such



226


i n t e r a c t i o n s may l e a d t o c e l l u l a r d e a t h , the i n h i b i t i o n of c e l l u l a r d i v i s i o n and thus m u l t i p l i c a t i o n o r , a t a minimum, mutagenic e f f e c t s . I n m u l t i c e l l u l a r organisms, t h e p h o t o s e n s i t i z e d e f f e c t s are expected t o be l i m i t e d t o dermal and subdermal t i s s u e s , i . e . , l i m i t e d by the degree o f l i g h t p e n e t r a t i o n . I n mammals, p a r t i c u l a r l y , such I n t e r a c t i o n s may be t o x i c o l o g i c a l i n t h a t s e v e r e t i s s u e damage occurs (erythema, s k i n b l i s t e r i n g , c a r c i n o g e n i c i t y ) o r pharmacological i n that f u r a n o c o u m a r i n - l i g h t - t i s s u e i n t e r a c t i o n s result i n desired medicinal effects ( v i t i l i g o , p s o r i a s i s ) . The r a t e of furanocoumarin metabolism by any organism almost c e r t a i n l y governs the s e v e r i t y and d u r a t i o n of the p h o t o b i o l o g i c a l a c t i o n s a s s o c i a t e d w i t h these compounds. T h i s c o n c l u s i o n seems j u s t i f i e d i n t h a t e s s e n t i a l l y any l i k e l y m e t a b o l i c t r a n s f o r m a t i o n can be expected t o r e s u l t i n s i g n i f i c a n t o r t o t a l d i m i n u t i o n o f p h o t o r e a c t i v i t y and/or an i n c r e a s e d tendency toward r a p i d e x c r e t i o n . A r y l h y d r o x y l a t l o n o r O - a l k y l h y d r o l y s i s r e a c t i o n s render furanocoumarins p h o t o b i o l o g i c a l l y i n a c t i v e (8) and, on s t r u c t u r a l grounds, f u r a n o r pyrone r i n g cleavage should r e s u l t I n i n a c t i v e ( a l t h o u g h not y e t e s t a b l i s h e d e x p e r i m e n t a l l y ) and e a s i l y e x c r e t e d metabolites. C e r t a i n of the p o t e n t i a l i n t e r m e d i a t e s i n f u r a n o c o u m a r i n metabolism might, i n f a c t , r e t a i n p h o t o b i o l o g i c a l a c t i v i t y ( i . e . , t h e 4 , 5 - e p o x i d e , the quinone, and t h e 3,4-dihydro d e r i v a t i v e s , F i g u r e 2 ) . However, such compounds would be r a p i d l y subjected to a d d i t i o n a l degradation r e a c t i o n s . With 4 , 5 , 8 - t r i m e t h y l p s o r a l e n , mammalian metabolism a p p a r e n t l y i n v o l v e s methyl group o x i d a t i o n t o a g r e a t e r e x t e n t than r i n g c l e a v a g e ( i f indeed r i n g c l e a v a g e r e a c t i o n s o c c u r a t a l l ) , b u t the major metabolite (5'-carboxy dimethylpsoralen) i s p h o t o b i o l o g i c a l l y i n a c t i v e (77) and r e a d i l y e x c r e t e d . Reduced b i o l o g i c a l a c t i v i t y o f furanocoumarin m e t a b o l i t e s has a l s o been I n d i c a t e d by an observed r e d u c t i o n i n photomutagenic a c t i v i t y o f x a n t h o t o x i n a f t e r i n c u b a t i o n w i t h r a t l i v e r mixed f u n c t i o n oxidase enzymes ( 8 5 ) . The metabolism of furanocoumarins by h i g h e r organisms appears to be, almost u n i v e r s a l l y , q u i t e r a p i d . I n o r a l l y - d o s e d rodents and I n man, peak plasma l e v e l s of absorbed x a n t h o t o x i n u s u a l l y o c c u r w i t h i n 1-2 h o u r s , f o l l o w e d by r a p i d d e p l e t i o n (67,74,75). M e t a b o l i t e s a r e q u i c k l y , and p r i m a r i l y , e l i m i n a t e d i n the u r i n e (68,74,75). S i m i l a r l y , r a p i d r a t e s o f m e t a b o l i c d e t o x i f i c a t i o n and e x c r e t i o n a r e seen i n dogs ( 7 1 ) , t h e goat ( 7 2 ) , and i n b i r d s ( P a n g i l i n a n , N. C ; I v i e , G. W.; u n p u b l i s h e d d a t a ) . Even i n I n s e c t s not adapted t o d i e t a r y furanocoumarins (S. f r u g i p e r d a ) , m e t a b o l i s m and e x c r e t i o n a r e q u i t e r a p i d , a l t h o u g h f a r l e s s so than f o r t h e f u r a n o c o u m a r i n t o l e r a n t P. p o l y x e n e s . S i x hours a f t e r o r a l treatment o f S. f r u g i p e r d a w i t h x a n t h o t o x i n , o n l y about 6% of t h e a d m i n i s t e r e d dose remains u n e x c r e t e d as the parent compound ( 8 1 ) . A l t h o u g h furanocoumarins a r e i n g e n e r a l much more b i o l o g i c a l l y a c t i v e i n t h e presence of l o n g w a v e l e n g t h UV l i g h t , these compounds do have demonstrable l i g h t - i n d e p e n d e n t a c t i o n s ( v i d e s u p r a ) . It i s , i n g e n e r a l , p o o r l y known t o what extent b i o t r a n s f o r m a t i o n s might a f f e c t such a c t i o n s , a l t h o u g h i t i s p r o b a b l y t r u e t h a t u l t i m a t e m e t a b o l i s m would u s u a l l y r e s u l t I n d e r i v a t i v e s of decreased b i o l o g i c a l a c t i v i t y (see F i g u r e 2 ) . However, r a t l i v e r enzymes, i n v i t r o , a p p a r e n t l y m e t a b o l i z e both x a n t h o t o x i n and 4,5',8-trimethyl=» p s o r a l e n t o mutagenic d e r i v a t i v e s ( 1 4 ) . A l s o , some s y n t h e t i c a n g u l a r furanocoumarins ( w i t h h y d r o p h i l l c s u b s t i t u e n t s a t the 4 1

f

1

f



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p o s i t i o n of the f u r a n r i n g ) a r e mutagenic i n the dark, but o n l y a f t e r microsomal a c t i v a t i o n ( 8 7 ) . The nature of the mutagenic m e t a b o l i t e s of such compounds i s unknown. That m e t h y l e n e d i o x y p h e n y l compounds s y n e r g i z e the t o x i c i t y of x a n t h o t o x i n t o H e l i o t h i s i n the dark (11) i m p l i e s t h a t the a c t i o n s of mixed f u n c t i o n o x i d a s e enzymes i n t h i s i n s e c t are p r i m a r i l y of a d e t o x i f i c a t i o n n a t u r e . The e f f e c t s of m e t a b o l i c a l t e r a t i o n s of p o t e n t i a l l y b i o l o g i c a l l y a c t i v e s u b s t i t u e n t m o i e t i e s of furanocoumarins i s a l s o p o o r l y u n d e r s t o o d . I t i s known t h a t the s y n t h e t i c furanocoumarin d e r i v a t i v e , p s o r a l e n g l y c i d y l e t h e r , Is a potent l i g h t independent mutagen, but t h a t the a c t i o n of epoxide h y d r o l a s e s reduces m u t a g e n i c i t y , c l e a r l y through h y d r o l y s i s of the epoxide moiety ( 8 6 ) . Conclusions Furanocoumarins have perhaps the w i d e s t documented spectrum of b i o l o g i c a l a c t i v i t i e s of any c l a s s of o r g a n i c c h e m i c a l s y e t s t u d i e d . Because of t h e i r major l i g h t - c a t a l y z e d mode of I n t e r a c t i o n w i t h l i v i n g m a t t e r , p r e s e n t l y w e l l d e f i n e d , furanocoumarins can p o t e n t i a l l y e x e r t p h o t o b i o c h e m i c a l i n f l u e n c e s on e s s e n t i a l l y any l i f e form. Furanocoumarins a l s o have s i g n i f i c a n t l i g h t - i n d e p e n d e n t a c t i o n s , by mechanisms t h a t a r e , a t p r e s e n t , e s s e n t i a l l y u n s t u d i e d . S t u d i e s of the b i o c h e m i c a l f a t e of furanocoumarins i n a number of v e r t e b r a t e and I n v e r t e b r a t e s p e c i e s have p r o v i d e d d a t a of c o n s i d e r a b l e v a l u e In e s t a b l i s h i n g how these c h e m i c a l s i n t e r a c t w i t h v a r i o u s l i f e forms and i n e x p l a i n i n g the r e l a t i v e p h o t o s e n s i t i v i t y of d i f f e r e n t s p e c i e s t o f u r a n o c o u m a r i n s . A d d i t i o n a l m e c h a n i s t i c and f a t e s t u d i e s a r e , however, c l e a r l y needed t o assess the p o t e n t i a l r o l e of non D N A - a l k y l a t i o n m o d e s - o f - a c t i o n ( i . e . , r e c e p t o r b i n d i n g ) on both the l i g h t - d e p e n d e n t and l i g h t - i n d e p e n d e n t a c t i o n s of these t o x i c o l o g l c a l l y , p h a r m a c o l o g i c a l l y , a g r i c u l t u r a l l y , and e n v i r o n m e n t a l l y s i g n i f i c a n t compounds. Literature 1. 2. 3. 4. 5. 6.

7. 8. 9. 10.

Cited

Perone, V. B. Microbial Toxins 1972, 8, 67-92. Towers, G. H. N. Can. J. Bot. 1984, 62, 2900-2911. Murray, R. D. H.; Mendez, J . ; Brown, S. A. The Natural Coumarins; Wiley: New York, 1982, 702 pp. Caporale, G.; Innocenti, G.; Guiotto, A.; Rodighiero, P.; Dall'Acqua, F. Phytochemistry, 1981, 20, 1283-1287. Innocenti, G.; Dall'Acqua, F.; Caporale, G. Phytochemistry 1983, 22, 2207-2209. Rodighiero, P.; Guitto, A.; Pastorini, G.; Manzini, P.; Dall'Acqua, F.; Innocenti, G.; Caporale, G. Gazz. Chim. Ital. 1980, 110, 167-172. Towers, G. H. N. Prog. Phytochem. 1980, 6, 183-202. Scott, B. R.; Pathak, M. A.; Mohn, G. R. Mutat. Res. 1976, 39, 29-74. Laskin, J . D.; Lee, E.; Yurkow, E. J . ; Laskin, D. L.; Gallo, M. A. Proc. Natl. Adad. S c i . 1985, 82, 6158-6162. Emerole, G.; Thabrew, M. I.; Anosa, V.; Okorie, D. A. Toxicology 1981, 20, 71-80.


228

11. 12. 13. 14.


15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29. 30. 31. 32. 33.

34. 35. 36. 37. 38. 39. 40.


Berenbaum, M.; Neal, J . J . J . Chem. Ecol. 1985, 11, 1349-1358. Bridges, B. A.; Mottershead, R. P. Mutat. Res. 1977, 44, 305-312. Wottawa, A.; Viernstein, H. Mutat. Res. 1981, 85, 298-299. Kirkland, D. J . ; Creed, K. L.; Mannisto, P. Mutat. Res. 1983, 116, 73-82. Quinto, I.; Averbeck, D.; Moustacchi, E.; Hrisoho, Z.; Moron, J. Mutat. Res. 1984, 136, 49-54. Uwaifo, A. O. L i f e S c i . Adv. 1984, 3, 62-70. Knox, J . P.; Dodge, A. D. Phytochemistry 1985, 24, 889-896. Tamaro, M.; Babudri, N.; Pani, B.; Baccichetti, F.; Rodighiero, P. Med. B i o l . Environ. 1983, 11, 493-497. Vedaldi, D.; Dall'Acqua, F.; Rodighiero, G. Med. B i o l . Environ. 1983, 11, 507-508. Vedaldi, D., Dall'Acqua, F.; B o l l e t t i n , P.; Rodighiero, G. Med. B i o l . Environ. 1984, 12, 569-573. Potapenko, A. Y.; Sukhorukov, V. L.; Davidov, B. V. Experientla 1984, 40, 264-265. Ivie, G. W. J . Agric. Food Chem. 1978, 26, 1394-1403. Fowlks, W. L.; G r i f f i t h , D. G.; Oginsky, E. L. Nature 1958, 181, 571-572. F u j i t a , H.; I s h i i , N.; Suzuki, K. Photochem. Photobiol. 1984, 39, 831-834. Berenbaum, M. Science 1978, 201, 532-534. Philogene, B. J . R.; Arnason, J. T.; Duval, F. Can. Entomol. 1985, 117, 1153-1157. Kagan, J . ; Chan, G. Experientla 1983, 39, 402-403. I v i e , G. W. In Effects of Poisonous Plants on Livestock; Keeler, K.; Van Kampen, K.; James, L. Ed.; Academic: New York, 1978, p 475. Camm, E. L., Wat, C.-K.; Towers, G. H. N. Can. J . Bot. 1976, 54, 2562-2566. Schonberg, A.; L a t i f , N. J . Am. Chem. Soc. 1954, 76, 6208. Marston, A.; Hostettmann, K. Phytochemistry 1985, 24, 639-652. Reshad, H.; Challoner, F.; Pollock, D. J . ; Baker, H. B r i t . J . Dermatol. 1984, 110, 299-305. Stern, R. S.; Laird, N.; Melski, J . ; Parrish, J . A.; F i t z p a t r i c k , T. B.; Bleich, H. L. N. Engl. J . Med. 1984, 310, 1156-1161. Farber, E. M.; Abel, E. A.; Cox, A. J . Arch. Dermatol. 1983, 119, 426-431. Mandula, B. B.; Pathak, M. A.; Nakayama, Y.; Davidson, S. J . Br. J . Dermatol. 1978, 99, 687-692. Bickers, D. R.; Mukhtar, H.; Molica, J r . , S. J . ; Pathak, M. A. J. Invest. Dermatol. 1982, 79, 201-205. Tsambaos, D.; Vizethum, W., Goerz, G. Arch. Dermatol. Res. 1978, 263, 339-342. Woo, W. S.; Lee, C. K.; Shin, K. H. Planta Med. 1982, 45, 234-236. Yu, S. J . Pestic. Biochem. Physiol. 1984, 22, 60-68. Friedman, J . ; Rushkin, E.; Waller, G. R. J . Chem. Ecol. 1982, 8, 55-65.


15. 41. 42. 43.

44.


45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

68.

69.

IVIE

Furanocoumarins

229

Shimomura, H.; Sashida, Y.; Nakata, H.; Kawasaki, J . ; Ito, Y. Phytochemistry 1982, 21, 2213-2215. Ivie, G. W.; Holt, D. L.; Ivey, M. C. Science 1981, 213, 909-910. Beier, R. C.; Ivie, G. W.; O e r t l i , E. H. In Xenobiotics i n Foods and Feeds; Finley, J. W.; Schwass, D. E., Ed.; ACS Symp. Ser. 234, 1983; Chapter 19, p 295. Gebreyesus, T.; Chapya, A. Curr. Themes Trop. S c i . 1983, 2, 237-242. Yajima, T.; Kato, N.; Munakata, K. Agric. B i o l . Chem. 1977, 41, 1263-1268. Yajima, T.; Munakata, K. Agric. B i o l . Chem. 1979, 43, 1701-1706. Muckensturm, B.; Duplay, D.; Robert, P. C.; Simonis, M. T.; Kienlen, J. C. Biochem. Syst. Ecol. 1981, 9, 289-292. Stadler, E.; Buser, H.-R. Experientla 1984, 40, 1157-1159. Berenbaum, M. Ecol. Entomol. 1981, 6, 345-351. Ashkenazy, D.; Kashman, Y.; Nyska, A.; Friedman, J . J . Chem. Ecol. 1985, 11, 231-239. Adams, R.; Boyle, J . ; Lever, R.; McQuillan, I.; MacKie, R. Scott. Med. J . 1982; 27, 264. Farr, P. M.; Ive, F. A. Br. J . Dermatol. 1984, 110, 347-350. James, M. P. C l i n . Exp. Dermatol. 1982, 7, 311-320. V e l l a B r i f f a , D.; Eady, R. A. J . ; James, M. P.; Gatti, S.; Bleehen, S. S. Br. J . Dermatol. 1983, 109, 67-75. Kenicer, K. J . A.; Lakshmipathi, T. Br. J . Dermatol. (Suppl.) 1982, 107, 48-49. Powell, F. C.; Spiegel, G. T.; Muller, S. A. Mayo C l i n . Proc. 1984, 59, 538-546. Paul, R.; Jansen, C. T. Dermatologica 1983, 167, 283-285. Wantzin, G. L.; Thomsen, K. Br. J . Dermatol. 1982, 107, 687-690. Ortonne, J . P.; Thivolet, J . ; Sannwald, C. Br. J . Dermatol. 1978, 99, 77-88. Anderson, T. F.; Voorhees, J . J . Annu. Rev. Pharmacol. Toxicol. 1980, 20, 235-257. Knudsen, E. A. Acta Derm. Venereol. 1980, 60, 452-456. Thiers, B. H. J . Am. Acad. Dermatol. 1982, 7, 811-816. Claudy, A. L.; Gagnaire, D. Acta Derm. Venereol. 1980, 60, 171-172. Claudy, A. L.; Gagnaire, D. Arch. Dermatol. 1983, 119, 975-978. Edelson, R.; Berger, C.; Gasparro, F.; Lee, K.; Taylor, J . C l i n . Res. 1983, 31, 467A. Nozu, T.; Suwa, T.; Migita, Y.; Tanaka, I. So Oyo Yakuri 1979, 18, 497-505. Smyth, R. D.; Van Harken, D. R.; Pfeffer, M.; Nardella, P. A.; Vasiljev, M.; Pinto, J. S.; Huttendorf, G. H. Arzneim.-Forsch./Drug Res. 1980, 30, 1725-1730. Mays, D. C.; Rogers, S. L.; Guiler, R. C.; Sharp, D. E.; Hecht, S. G.; Staubus, A. E.; Gerber, N. J . Pharmacol. Exp. Ther. 1986, 236, 364-373. Warner, W.; Giles, A.; Brouwer, E.; Kornhauser, A. C l i n . Res. 1980, 28, 584A.


230 70. 71. 72. 73.


74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87.


Sharp, D. E.; Mays, D. C.; Rogers, S. L.; Guiler, R. C.; Hecht, S.; Gerber, N. Proc. West. Pharmacol. Soc. 1984, 27, 255-258. K o l i s , S.; Williams, T.; Postma, E.; Sasso, G.; Confalone, P.; Schwartz, M. Drug Metab. Dispos. 1979, 7, 220-225. Ivie, G. W.; Beier, R. C.; B u l l , D. L.; O e r t l i , E. H. Am. J . Vet. Res. 1986, 47, 799-803. Ehrsson, H.; Eksborg, S.; Wallin, I. Eur. J . Drug Metab. Pharmacokinet. 1978, 2, 125-128. Busch, U.; Schmld, J . ; Koss, F. W.; Zipp, H.; Zimmer, A. Arch. Dermatol. Res. 1978, 262, 255-265. Schmid, J . ; Prox, A.; Reuter, A.; Zipp, H.; Koss, F. W. Eur. J. Drug Metab. Pharmacokinet. 1980, 5, 81-92. Stolk, L. M. L.; Westerhof, W.; Cormane, R. H.; Van Zwieten, P. A. Br. J . Dermatol. 1981, 105, 415-420. Mandula, B. B.; Pathak, M. A.; Dudek, G. Science 1976, 193, 1131-1134. Mandula, B. B.; Pathak, M. A. Biochem. Pharmacol. 1979, 28, 127-132. Ashwood-Smith, M. J . ; Ring, R. A.; Liu, M.; P h i l l i p s , S.; Wilson, M. Can. J . Zool. 1984, 62, 1971-1976. Ivie, G. W.; B u l l , D. L.; Beier, R. C.; Pryor, N. W.; O e r t l i , E. H. Science 1983, 221, 374-376. B u l l , D. L.; Ivie, G. W.; Beier, R. C.; Pryor, N. W.; O e r t l i , E. H. J . Chem. Ecol. 1984, 10, 893-911. Berenbaum, M.; Feeny, P. Science 1981, 212, 927-929. Ivie, G. W.; B u l l , D. L.; Beier, R. C.; Pryor, N. W. J . Chem. Ecol. 1986, 12, 871-884. B u l l , D. L.; Ivie, G. W.; Beier, R. C.; Pryor, N. W. J . Chem. Ecol. 1986, 12, 885-892. Schimmer, O.; Fischer, K. Mutat. Res. 1980, 79, 327-330. Ivie, G. W.; MacGregor, J . T.; Hammock, B. D. Mutat. Res. 1980, 79, 73-77. Monti-Bragadin, C.; Tamaro, M.; Venturini, S.; Pani, B.; Babudri, N.; Baccichetti, F. Farmaco Ed. S c i . 1981, 36, 551-556.

R E C E I V E D January13,1987


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