1 Overview: The Influence of Nutrition on Xenobiotic Metabolism D. E. SCHWASS1,3 and J. W. FINLEY2 U.S. Department of Agriculture, Western Regional Research Center, Berkeley, CA 94610 Nabisco Brands, Inc., Fair Lawn,NJ07410
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In the course of living in the modern world it is inevitable that man and animals will be exposed to compounds in the environment which are not essential for life or even "normal" from the standpoint of the evolution of the species. The term "xenobiotic" (from the Greek "xenos" and "bios", meaning stranger to life) was coined by Mason, et al (1) to describe the myriad of compounds including carbohydrates, lipids, proteins, alkaloids, natural and synthetic drugs, flavorings, pigments, preservatives, polycyclic hydrocarbons, flavonoids, terpenoids, etc., which may enter the organism as non-essential or non-functional materials. The assumption inherent in the use of the term is that one is speaking relative to an organism of reference. For example, the drug quinine is a xenobiotic relative to man but not to the South American tree, Chinchona officinalis, in which quinine is a major constituent of the bark. Xenobiotics which enter the biosphere of the organism are not necessarily toxic. In fact, based on the Mason definition, non-essential amino acids could be referred to as xenobiotics. For the purpose of this symposium, however, xenobiotic does not include non-essential nutrients which occur in the diet, but will be restricted to environmental compounds which are acutely toxic, potentially toxic requiring activation, or which exhibit long term effects, such as mutagens, carcinogens or teratogens. In general, the discussions in this symposium are relative to man and/or animals. It is important to remember that xenobiotics range from the inocuous (i.e. vanillin) through the chronically toxic (i.e. ethanol) to the acutely toxic (i.e. curare). Some xenobiotics, although not toxic in and of themselves, are metabolically converted to toxic substances. The metabolic conversion of xenobiotics to toxic substances can be dramatically influenced by the nutritional status of the organism. Smoking, drugs, industrial chemicals and foods, represent the major sources of exposure to xenobiotics for modern man. Because diet furnishes the most variable and continuous array of xenobiotic exposure, the emphasis of this symposium is the 3
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Finley and Schwass; Xenobiotic Metabolism: Nutritional Effects ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
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XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS
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i n f l u e n c e of food-borne x e n o b i o t i c s and how d i e t can mediate the m e t a b o l i s m of t h e s e compounds. Food borne x e n o b i o t i c s c a n be endogenous t o the f o o d s t u f f ( f l a v i n o i d s i n t e a ) , can r e s u l t from p r o c e s s i n g and s t o r a g e ( l i p i d o x i d a t i o n o r non-enzymatic browning) or can be the r e s u l t of d e l i b e r a t e a d d i t i o n ( t h e antioxidant, butylated hydroxyanisole). Exposure t o x e n o b i o t i c s i s i n e v i t a b l e and a l t h o u g h the degree of exposure can be c o n t r o l l e d , i t i s i m p o s s i b l e t o p r e v e n t exposure a l t o g e t h e r . F o r t u n a t e l y , the h e a l t h y , w e l l - n o u r i s h e d i n d i v i d u a l o r a n i m a l under normal c i r c u m s t a n c e s can r e s i s t l o n g term e f f e c t s of many of t h e s e compounds by m e t a b o l i z i n g them and e x c r e t i n g them as m e t a b o l i t e s o r c o n j u g a t e s of m e t a b o l i t e s . A major s o u r c e of exposure to x e n o b i o t i c s i s tobacco smoke. C i g a r e t t e smoke c o n s i s t s of a l a r g e v a r i e t y o f compounds i n c l u d i n g o x i d a n t s , f r e e r a d i c a l s , b e n z o - ( a ) - p y r e n e and c a r b o n monoxide. Long term exposure t o c i g a r e t t e smoke e n t a i l s exposure t o both a c u t e l y t o x i c m a t e r i a l s and c h r o n i c a l l y t o x i c m a t e r i a l s . We a r e a l l exposed t o smoke i n v a r i o u s degrees b o t h from t o b a c c o and from the environment through the b u r n i n g of f u e l s and from c o o k i n g . Exposure t o i n d u s t r i a l s o u r c e s of x e n o b i o t i c s c a n come v i a the a i r o r through exposure and a b s o r p t i o n by the s k i n . A l t h o u g h major i n d u s t r i a l exposure r e c e i v e s much p u b l i c i t y when i t o c c u r s . T h i s t y p e of event u s u a l l y a c c o u n t s f o r exposure t o r e l a t i v e l y few compounds over a p r o l o n g e d p e r i o d of t i m e . F o r t u n a t e l y , c h e m i c a l companies have made g r e a t s t r i d e s i n r e d u c i n g the i n c i d e n c e of such exposure, a l t h o u g h i t i s l i k e l y t h a t some exposure w i l l c o n t i n u e t o o c c u r e i t h e r through a c c i d e n t s o r l a c k of knowledge. I n d u s t r i a l p o l l u t i o n i n the form of t o x i c waste s h o u l d be reduced s i g n i f i c a n t l y i n the next s e v e r a l y e a r s as e f f o r t s c o n t i n u e t o c o r r e c t t h i s problem. Exposure from t o x i c waste dumps i s l i k e l y t o c o n t i n u e but a t lower l e v e l s . P h a r m a c e u t i c a l drugs c a n be c o n s i d e r e d x e n o b i o t i c s and i n the w e s t e r n w o r l d an i n d i v i d u a l might expect t o be exposed s i g n i f i c a n t l y t o t w o - t o - t h r e e dozen compounds i n a l i f e t i m e under normal c i r c u m s t a n c e s . F r e q u e n t l y t h e s e exposures a r e over r e l a t i v e l y short p e r i o d s of time. Food r e p r e s e n t s a l a r g e and c o n t i n u o u s exposure t o a v a s t a r r a y of x e n o b i o t i c s . X e n o b i o t i c s from f o o d c a n range from t h e inocuous to the e x t r e m e l y dangerous. P l a n t s f r e q u e n t l y produce a v a r i e t y of x e n o b i o t i c s which s u b s e q u e n t l y a r e consumed by man o r animals. I n a d d i t i o n , d u r i n g s t o r a g e and p r o c e s s i n g of f o o d s , ( i n c l u d i n g home c o o k i n g ) , x e n o b i o t i c s c a n be produced. A recent symposium ( F i n l e y and Schwass) (2) reviewed many of t h e s e s o u r c e s of x e n o b i o t i c s i n t h e d i e t . H i s t o r i c a l l y , the impact of d i e t on h e a l t h has been a c o n c e r n of man. I n r e c e n t y e a r s we have seen g r e a t e r emphasis on how n u t r i t i o n r e l a t e s t o h e a l t h and the p r e v e n t i o n of c h r o n i c a f f l i c t i o n s such as c o r o n a r y h e a r t d i s e a s e , h y p e r t e n s i o n , o b e s i t y , and c a n c e r . C o n s e q u e n t l y , s e v e r a l h e a l t h o r g a n i z a t i o n s have proposed g u i d e l i n e s t o promote b e t t e r h e a l t h and reduce r i s k
Finley and Schwass; Xenobiotic Metabolism: Nutritional Effects ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
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SCHWASS AND FINLEY
Overview
of c h r o n i c d i s e a s e *
The N a t i o n a l R e s e a r c h C o u n c i l
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(3) p u b l i s h e d an e x t e n s i v e study and g u i d e l i n e s r e g a r d i n g n u t r i t i o n a l means t o reduce t h e r i s k of c a n c e r . I n t h i s volume, Palmer (^) d i s c u s s e s t h e s e g u i d e l i n e s i n terms o f c u r r e n t e v i d e n c e . One o f the problem a r e a s d i s c u s s e d i s d i e t a r y f a t and i t s r e l a t i o n s h i p t o c a n c e r as w e l l as p r e v i o u s l y e s t a b l i s h e d r e l a t i o n s h i p s t o c o r o n a r y h e a r t d i s e a s e and o b e s i t y . Throughout t h i s symposium one o b s e r v e s a common t h r e a d i n many of t h e p a p e r s : the many problems a s s o c i a t e d w i t h l i p i d s i n the d i e t . I t i s important t o n o t e however, t h a t the problems may not be due s i m p l y t o f a t but more l i k e l y t o o x i d i z e d l i p i d products. P r y o r (2) r e v i e w s the mechanisms o f l i p i d o x i d a t i o n and d i s c u s s e s t h e c h e m i c a l b a s i s f o r a r e l a t i o n s h i p between l i p i d o x i d a t i o n and c h r o n i c d i s e a s e . I t would seem from t h i s and o t h e r evidence (D (§) t h a t p e r o x i d i z i n g l i p i d s c o u l d be a major d i e t a r y c o n c e r n i n the development o f c e r t a i n t y p e s o f c a n c e r s . I f one c o n s i d e r s t h e e a r l y s t a g e s o f tumor development t o be i n i t i a t i o n f o l l o w e d by promotion, one c o u l d s p e c u l a t e a number o f roles for peroxidizing l i p i d s . I n i t i a t i o n f o r the purpose o f t h i s d i s c u s s i o n w i l l be c o n s i d e r e d t h e i n i t i a l c h e m i c a l change i n the DNA o f a c e l l which has the p o t e n t i a l t o l e a d t o t h e development o f a tumor. I n t h e p r o m o t i o n s t a g e , t h e damaged c e l l b e g i n s t o m u l t i p l y as a r e s u l t o f c h e m i c a l i n s u l t and tumor development p r o c e e d s . The i n i t i a l damage o r i n i t i a t i o n c a n be caused by a v a r i e t y o f compounds, many o f which a r e used a s model compounds f o r t h e study o f c a r c i n o g e n e s i s . One might s p e c u l a t e t h a t these compounds ( i . e . , DMBA, b e n z o - ( a ) - p y r e n e ) c o u l d a c t a s i n i t i a t o r s and t h e o x i d i z i n g l i p i d s as promoters. Indeed, much of t h e e v i d e n c e i n the p r e s e n t symposium w i l l support t h i s speculation. I f one then c o n s i d e r s t h e p r o t e c t i v e r o l e a g a i n s t tumor development o f r e t e n o i d s , BHT, a s c o r b i c a c i d and t o c o p h e r o l , a l l o f which a r e a n t i o x i d a n t s , t h e argument i s s t r e n g t h e n e d (Chow, (1) (JO: K i n g , ; Newberne.
