Light-Activated Pesticides - ACS Publications - American Chemical

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.

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

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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.

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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.


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