Xenobiotic Metabolism: Nutritional Effects - ACS Publications

17 Food and Drug Interactions

Downloaded by NORTH CAROLINA STATE UNIV on May 3, 2015 | http://pubs.acs.org Publication Date: May 6, 1985 | doi: 10.1021/bk-1985-0277.ch017

C. JELLEFF CARR Carr Associates, 6546 Belleview Drive, Columbia, MD 21046

Nutritional status determines effects of therapeutic drugs and recognition of these factors should lead to improved drug therapy. Pharmacokinetics are changed by a person's diet but metabolic tissue and cellular effects are not well understood. Biochemical transformations and enzyme inductions that decrease or increase toxicity of drugs are discussed and numerous examples given. The old adage, we are what we eat, needs a new and more attractive label. We are just beginning to recognize that the composition of our diet can have a remarkable influence on a wide variety of metabolic changes. This subject requires more interest on the part of the scientific and medical community (1). The nutritional status of a person will determine in large measure the degree of undesirable effects of therapeutic drugs and the growing literature on the impact of nutritional and environmental substances on the disposition and therapeutic efficacy of drugs reflects a complex of biochemical and pharmacologic interactions. Recognition and understanding of these reactions should lead to improved drug therapy. However, in recent years it has become clear that the impact of nutritional and environmental substances on the disposition of drugs is difficult to predict. Biochemical and pharmacologic interactions between food components, additives, chemicals and therapeutic drugs are now under study not only for their toxicologic significance, but because understanding these reactions should lead to improved drug therapy. Absorption and utilization of drugs given orally is influenced significantly in some instances by different foods. Pharmacokinetic studies indicate plasma levels changed by the diet may be crucial for those drugs where the blood concentration must be kept within a narrow range. These are relatively elementary facts related to efficient drug therapy and wisely observed by the careful physician. On the other hand, metabolic changes and tissue interactions at the cellular level of drug actions are more arcane and frequently not recognized, indeed, are often not known. Biochemical transformations at the target cell sites, the 0097-6156/85/0277-0221S06.00/0 © 1985 American Chemical Society

In Xenobiotic Metabolism: Nutritional Effects; Finley, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.


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p h a r m a c o k i n e t i c changes, m e t a b o l i c s i g n i f i c a n c e and the d e t o x i f i c a t i o n and e x c r e t i o n o f drugs as m o d i f i e d by n u t r i t i o n a l i n f l u e n c e s a r e coming under s t u d y . We r e c o g n i z e t h a t t h e r a p e u t i c e f f i c a c y and drug t o x i c i t y may be d i r e c t l y i n f l u e n c e d by f o o d - d r u g i n t e r a c t i o n s , howe v e r , r e l a t i v e l y few i n v e s t i g a t o r s pursue s t u d i e s to d e v e l o p the n e c e s s a r y knowledge r e q u i r e d t o u n d e r s t a n d t h e s e r e l a t i o n s h i p s . A r e l a t i v e l y new n o t e on t h i s s u b j e c t has been added by the d e v e l o p i n g knowledge o f n o n - n u t r i e n t f o o d a d d i t i v e s . These subs t a n c e s a l s o may change the p h a r m a c o k i n e t i c s o f t h e r a p e u t i c d r u g s . W i t h i n c r e a s i n g c o n c e r n about c a r c i n o g e n s i n the f o o d s u p p l y and w i t h more s e n s i t i v e a n a l y t i c a l methodology, t h e s e c h e m i c a l b i o t r a n s f o r m a t i o n s i n man a r e b e i n g s t u d i e d i n terms o f d i e t a r y f a c t o r s t h a t i n f l u e n c e the a c t i o n o f d r u g s . The most r e c e n t c o n c e r n , f o r example, has been t r a c e s o f the s o i l fumigant e t h y l e n e d i b r o m i d e (EDB) i n f o o d s a r i s i n g from a g r i c u l t u r a l a p p l i c a t i o n s . D i e t a r y m o d i f i c a t i o n s a r e brought about by use o f w e i g h t r e d u c i n g d i e t s , v e g e t a r i a n d i e t s , h o s p i t a l i z a t i o n , or p o s t - o p e r a t i v e r e g i m e n s . These d i e t s a r e o f t e n c o n t i n u e d f o r l o n g p e r i o d s o f time and i t i s l i k e l y they r e s u l t i n changes i n the m e t a b o l i s m by the body of s u b s e q u e n t l y a d m i n i s t e r e d d r u g s . We know t h a t drug metabol i s m r a t e s i n the e l d e r l y a v e r a g e o n e - h a l f t o t w o - t h i r d s the r a t e o b s e r v e d i n younger p e o p l e . However, i n d i v i d u a l v a r i a t i o n s a r e g r e a t and an o l d p e r s o n may have m e t a b o l i c r a t e s w e l l w i t h i n the v a l u e n o r m a l f o r younger p e r s o n s . Thus, g e n e r a l i z a t i o n s cannot be drawn because the e l d e r l y , who as a group consume the g r e a t e s t numb e r o f d r u g s , a r e f a r from a homogeneous p o p u l a t i o n . I t i s of i n t e r e s t t h a t d r u g r e g u l a t o r y g u i d e l i n e s do not a d d r e s s t h e s e i s s u e s . G e n e r a l l y s p e a k i n g , the p h y s i c i a n o r the n u t r i t i o n a l b i o c h e m i s t i s confronted w i t h a complicated c l i n i c a l p i c t u r e of m u l t i p l e disease e n t i t i e s , m u l t i p l e d r u g t h e r a p y , and a poor d i e t a r y regimen i n the elderly. E f f e c t o f Foods on B i o c h e m i c a l T r a n s f o r m a t i o n of Drugs L i v i n g c e l l s have a r e m a r k a b l e c a p a c i t y t o c h e m i c a l l y m o d i f y d r u g molecules. The b i o c h e m i c a l t r a n s f o r m a t i o n f r e q u e n t l y a c h i e v e d by the n o n - s p e c i f i c enzymes p r e s e n t i n the microsomes o f c e l l s i s one o f t h e c h i e f o x i d a t i v e pathways drug m o l e c u l e s undergo. These a r e u s u a l l y h y d r o x y l a t i o n r e a c t i o n s l e a d i n g to d e t o x i f i c a t i o n o f the d r u g . More p o l a r m e t a b o l i t e s a r e formed and hence a r e l e s s c a p a b l e o f p e n e t r a t i n g the l i p i d t a r g e t c e l l b a r r i e r . The r e s u l t i s subsequent e x c r e t i o n o f t h e l e s s t o x i c m e t a b o l i t e s . The mechanism i n h e p a t i c c e l l u l a r m e t a b o l i s m i n v o l v e s an e l e c t r o n t r a n s p o r t system t h a t f u n c t i o n s f o r many drugs and c h e m i c a l s u b s t a n c e s . These r e a c t i o n s i n c l u d e O - d e m e t h y l a t i o n , N-demethylat i o n , h y d r o x y l a t i o n , n i t r o r e d u c t i o n and o t h e r c l a s s i c a l b i o t r a n s formations. The e l e c t r o n t r a n s p o r t system c o n t a i n s the heme p r o t e i n , cytochrome P-450 t h a t i s r e d u c e d by NADPH v i a a f l a v o p r o t e i n , cytochrome P-450 r e d u c t a s e . For o x i d a t i v e metabolic r e a c t i o n s , cytochrome P-450, i n i t s r e d u c e d s t a t e (Fe ) , i n c o r p o r a t e s one atom o f oxygen i n t o the d r u g s u b s t r a t e and a n o t h e r i n t o w a t e r . Many m e t a b o l i c r e d u c t i v e r e a c t i o n s a l s o u t i l i z e t h i s system. I n a d d i t i o n , t h e r e i s a l i p i d component, p h o s p h a t i d y l c h o l i n e , which i s a s s o c i a t e d w i t h the e l e c t r o n t r a n s p o r t and i s an o b l i g a t o r y r e q u i r e m e n t f o r 2



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Food and Drug Interactions

drug m e t a b o l i s m . I t i s o b v i o u s t h a t i n such a complex s e r i e s o f e v e n t s the f o o d , d r u g , o r c h e m i c a l elements c o u l d p a r t i c i p a t e i n a v a r i e t y o f ways. I t must be p o i n t e d out t h a t not a l l enzymic r e a c t i o n s of drugs i n l i v e r c e l l s produce l e s s t o x i c m e t a b o l i t e s some a r e more t o x i c H e p a t i c drug m e t a b o l i z i n g enzymes a c t i v a t e some c h e m i c a l l y s t a b l e drugs to p o t e n t a l k y l a t i n g , a r y l a t i n g or a c y l a t i n g a g e n t s . These b i n d c o v a l e n t l y to l i v e r c e l l macromolecules and may cause n e c r o s i s ( l a , 2 ) . Foods y i e l d p r o t e c t i v e s u b s t a n c e s such as g l u t a t h i o n e * t h a t a r e c a p a b l e of c o n j u g a t i n g w i t h a t o x i c m e t a b o l i t e . However, when body s t o r e s o f t h e s e s u b s t a n c e s a r e exhausted the t o x i c i t y o f chemic a l s u b s t a n c e s can be i n c r e a s e d . Thus, n u t r i t i o n can g r e a t l y i n f l u e n c e the a c t i v i t y o f t h e s e i m p o r t a n t m e t a b o l i c systems ( 3 ) . The r a t e s o f t o x i c a t i o n o r d e t o x i c a t i o n of drugs and xenob i o t i c s i n a n i m a l s and man a r e known to be i n f l u e n c e d by age, sex, s p e c i e s , s t r a i n , d i s e a s e and d i e t . One r e s e a r c h r e p o r t l i s t s 10 f a c t o r s (3a). I t appears t h a t f o r man, d i e t i s most v a r i e d and t h e r e f o r e most complex as a v a r i a b l e i n a s c e r t a i n i n g i t s r o l e i n e i t h e r e n h a n c i n g t o x i c i t y or r e d u c i n g untoward e f f e c t s of t h e r a p e u t i c drugs o r e n v i r o n m e n t a l c h e m i c a l s . F o l l o w i n g the p r o l o n g e d a d m i n i s t r a t i o n of some d r u g s , h e p a t i c m i c r o s o m a l enzymes may be s t i m u l a t e d and the p r o c e s s o f " i n d u c t i o n " takes place (4,5). The i m p l i c a t i o n s of m i c r o s o m a l enzyme i n d u c t i o n a r e j u s t b e g i n n i n g to be a p p r e c i a t e d by c l i n i c i a n s . Indeed, t h i s phenomenon e x p l a i n s why i n some c a s e s r e p e a t e d drug dosage may l e a d t o d e c r e a s e d t h e r a p e u t i c e f f e c t i v e n e s s . F o r example, the d e t o x i f i c a t i o n mechanisms o f the l i v e r become more e f f i c i e n t i n m e t a b o l i z i n g the drug and l a r g e r doses a r e r e q u i r e d t o e l i c i t the d e s i r e d c l i n i c a l p h a r m a c o l o g i c e f f e c t s . M i c r o s o m a l enzymes can a l s o be i n duced by d i e t i n such t i s s u e s as the i n t e s t i n e , l u n g , a d r e n a l s and k i d n e y a l t h o u g h l e s s i s known about t h e s e e x t r a - h e p a t i c systems (6-9). T o x i c o l o g i c a l S i g n i f i c a n c e of Enzyme

Induction

A l o n g s e r i e s o f e x p e r i m e n t s has demonstrated t h a t many p l a n t f o o d s s e r v e as i n d u c e r s o f b o t h l i v e r and g a s t r o i n t e s t i n a l h y d r o x y l a s e s (10,11). Enhanced a c t i v i t y o f some m i c r o s o m a l enzymes o r i n d u c t i o n o f i n c r e a s e d a r y l h y d r o c a r b o n h y d r o x y l a s e a c t i v i t y by f o o d a d d i t i v e s o r n a t u r a l l y - o c c u r r i n g f l a v o n e s , has been shown to i n h i b i t the a c t i o n o f c h e m i c a l c a r c i n o g e n s i n a n i m a l s . These i n h i b i t o r s i n c l u d e b o t h n a t u r a l f o o d i n g r e d i e n t s , d r u g s , or s y n t h e t i c compound i n t r o d u c e d i n t o the environment ( 1 1 ) . Phenobarbital, diphenylhydan t o i n , p h e n y l b u t a z o n e , and p r e g n e n o l o n e - 1 6 - c a r b o n i t r i l e a r e examples o f drugs t h a t i n d u c e h e p a t i c m i c r o s o m a l enzymes ( 1 2 ) . The s i g n i f i c a n c e o f t h e s e f i n d i n g s l i e s i n the a p p a r e n t p r o t e c t i v e e f f e c t s o f t h e s e and r e l a t e d s u b s t a n c e s i n i n d u c i n g i n c r e a s e d m i c r o s o m a l monooxygenase a c t i v i t y . The wide range of compounds c a p a b l e o f i n d u c i n g t h i s p r o t e c t i v e e f f e c t a g a i n s t known p o t e n t c a r c i n o g e n s i s noteworthy. Many o f t h e s e s u b s t a n c e s a r e p r e s e n t i n p l a n t s consumed by man as f o o d . These i n c l u d e the f l a vones of n a t u r a l o r i g i n , e.g. 5 , 6 - b e n z o f l a v o n e , and r u t i n from the buckwheat f a m i l y . N a t u r a l i n d o l e s i n the e d i b l e v e g e t a b l e s B r u s s e l s p r o u t s , cabbage, c a u l i f l o w e r and b r o c c o l i , a r e i n h i b i t o r y to



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b e n z o ( a ) p y r e n e - i n d u c e d n e o p l a s i a i n the f o r e s t o m a c h o f r o d e n t s and a d d i t i o n of c e r t a i n of these i n d o l e s to t h e i r d i e t s i n h i b i t e d p u l monary adenoma, and mammary tumor f o r m a t i o n ( 1 3 ) . The mechanism(s) o f a c t i o n o f t h e s e i n d o l e s i s not known a t p r e s e n t . I n a d d i t i o n , p e s t i c i d e r e s i d u e s such as DDT and the f u n g i c i d e EDB p r e s e n t i n low l e v e l s i n man's f o o d s , w h i l e below the l e v e l t h a t c a u s e s enzyme i n d u c a t i o n i n r a t s , may a l s o c o n t r i b u t e to t o t a l metab o l i c drug e f f e c t s . The i n f l u e n c e s o f d i e t and s o c i a l l y used drugs on drug o x i d a t i o n has been s t u d i e d i n v e g e t a r i a n s and n o n - v e g e t a r i a n s . Major d i f f e r e n c e s i n d i e t , c i g a r e t t e smoking, and use o f the s t e r o i d o r a l c o n t r a c e p t i v e s were shown to have s i g n i f i c a n t e f f e c t s on a n t i p y r i n e o x i d a t i o n (14,15). I f one can g e n e r a l i z e from a n t i p y r i n e t o o t h e r d r u g s , t h e s e e n v i r o n m e n t a l f a c t o r s c o u l d p l a y imp o r t a n t r o l e s i n d r u g t h e r a p y and p r e v e n t i o n o f t o x i c i t y . Obviously, i t i s d i f f i c u l t t o c o n t r o l f o r so many d i f f e r e n t v a r i a b l e s i n any p o p u l a t i o n group, but t h e f i n d i n g s emphasize p o i n t s t h a t r e q u i r e s t u d y f o r f o o d and drug i n t e r a c t i o n s . T o x i c s u b s t a n c e s , f o o d i n g r e d i e n t s and t h e r a p e u t i c drugs have an a l t e r e d t i s s u e d i s t r i b u t i o n depending on t h e d i e t . F o r example, splanchnic b l o o d f l o w i s m o d i f i e d by o r a l g l u c o s e o r p r o t e i n f e e d i n g and hence t h e t i s s u e s i t e o f a c t i o n o f t h e s e v a r i o u s s u b s t a n c e s can be m o d i f i e d ( 1 5 a ) . T i s s u e changes then can be i n d u c e d by a l t e r i n g b l o o d f l o w and the r e s u l t i n g p h a r m a c o l o g i c e f f e c t s , t i s s u e i n j u r y o r r e p a i r w i l l be changed. From a n i m a l s t u d i e s and from human e x p e r i e n c e we know t h a t h i g h f a t d i e t s promote t h e r a p i d a b s o r p t i o n o f s u b s t a n c e s from the g a s t r o intestinal tract. T h i s w i l l i n c l u d e drugs, t e s t substances i n a n i mal d i e t s , and f o o d i n g r e d i e n t s (15b). L i p i d d i e t s w i t h t h e i r s a t u r a t i o n , p o l y u n s a t u r a t i o n , and e s s e n t i a l f a t t y a c i d c o m p o s i t i o n m o d i f y n u t r i t i o n o f the p e r s o n and added a n t i - o x i d a n t s i n t h e s e o i l s a r e r e c o g n i z e d to i n f l u e n c e metabolism. The e x t e n s i v e l i t e r a t u r e i n t h i s f i e l d has been r e v i e w e d and c o m p i l e d by The N u t r i t i o n Foundation. One o f the noteworthy f i n d i n g s was the d e m o n s t r a t i o n by many i n v e s t i g a t o r s t h a t tumor p r o m o t i o n i s enhanced i n e x p e r i m e n t a l a n i m a l s by h i g h f a t d i e t s (15b). I n a d d i t i o n , we know t h a t changing a customary d i e t t o one h i g h i n p r o t e i n and low i n c a r b o h y d r a t e i n some p e o p l e , i n c r e a s e s t h e r a t e s o f m e t a b o l i s m o f drugs such as a n t i p y r i n e and t h e o p h y l l i n e , and s h i f t i n g t o an i s o c a l o r i c d i e t o f low p r o t e i n - h i g h c a r b o h y d r a t e slows the r a t e s o f m e t a b o l i s m o f t h e s e d r u g s . However, numerous s t u d i e s emphasize the c o n s i d e r a b l e i n d i v i d u a l v a r i a b i l i t y t o changes i n human d i e t s ; some p e o p l e e x h i b i t d r a m a t i c e f f e c t s o t h e r s e x h i b i t l i t t l e o r no r e s p o n s e . Metabolite Induction

Enhancing

Toxicity

L i v e r drug t o x i c i t y may be i n c r e a s e d by enzyme i n d u c e r s and a number o f examples a r e known. Thus, c a r b o n t e t r a c h l o r i d e ( 1 6 ) , t r i c h l o r e t h y l e n e ( 1 7 ) , t o l u e n e ( 1 8 ) , hycanthone ( 1 9 ) , acetaminophen and i s o n i a z i d ( 2 0 ) , and m e t o t r e x a t e ( 2 1 ) , among o t h e r drugs and chemic a l s , have been s t u d i e d i n t h i s r e s p e c t . The s i g n i f i c a n c e o f p o l y c y c l i c a r o m a t i c h y d r o c a r b o n s (PCH) formed i n c h a r c o a l - b r o i l e d beef has been p u b l i c i z e d w i t h r e s p e c t t o the a b i l i t y o f t h e s e s u b s t a n c e s t o a l t e r the f a t e o f drugs i n t h e



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body. The b i o a v a i l a b i l i t y o f p h e n a c e t i n i n human s u b j e c t s a p p a r e n t l y i s reduced (22) and the plasma c l e a r a n c e o f c a f f e i n e i n the r a t i s a l t e r e d ( 2 3 ) . Benzanthracene, d i b e n z a n t h r a c e n e , c h r y s e n e , and pyr e n e , p o t e n t i n d u c e r s of the cytochrome P-448 system i n l i v e r m i c r o somes, caused a marked i n c r e a s e i n the plasma c l e a r a n c e o f c a f f e i n e ( 2 3 ) . These f i n d i n g s suggest t h a t the metabolism o f many drugs may be a l t e r e d i n man exposed t o t h e s e e n v i r o n m e n t a l s u b s t a n c e s o r f o o d s c o n t a i n i n g PCH. Long-term a n t i c o n v u l s i v e t h e r a p y w i t h d i p h e n y l h y d a n t o i n o r p h e n o b a r b i t a l i s known t o cause o s t e o m a l a c i a by i n f l u e n c i n g c a l c i u m m e t a b o l i s m (24,25). A l t e r a t i o n i n the m e t a b o l i s m o f v i t a m i n D, presumably secondary t o i n d u c t i o n o f h e p a t i c microsomal enzymes, l e a d s t o the c a l c i u m and bone a b n o r m a l i t i e s ( 2 6 ) . P a t i e n t s on a n t i c o n v u l s i v e t h e r a p y w i t h p h e n y t o i n e x h i b i t a d e c r e a s e i n serum 25h y d r o x y v i t a m i n D (27) . Adequate d i e t a r y amounts o f v i t a m i n p r e c u r s o r s o r m i c r o s o m a l enzyme s t i m u l a t o r s might p r e v e n t t h e s e e f f e c t s of long-term therapy. The i n g e s t i o n o f f o o d s c o n t a i n i n g t y r a m i n e , such as cheese, and the h y p e r t e n s i v e c r i s i s produced i n p a t i e n t s t a k i n g the a n t i d e p r e s s i v e drug t r a n y l c y p r o m i n e i s a c l a s s i c example o f f o o d and drug toxicity. Tyramine-containing foods apparently s t i m u l a t e the r e l e a s e o f n o r e p i n e p h r i n e , which r e s u l t s i n a sharp e l e v a t i o n i n b l o o d p r e s s u r e . The n o r e p h i n e p h r i n e r e l e a s e i s a l s o a c c e l e r a t e d by the drug i t s e l f , a monoamine o x i d a s e i n h i b i t o r ( 2 8 ) . P a t i e n t s r e c e i v i n g the monoamine o x i d a s e i n h i b i t o r s a r e now c a u t i o n e d t o a v o i d the f o o d s t h a t a r e known t o c o n t a i n h i g h amounts o f t y r a m i n e , as r e s u l t o f this well-publicized interaction. The l i s t o f f o o d s t h a t c o n t a i n t y r a m i n e o r r e l a t e d amines c a p a b l e o f c a u s i n g t h e s e r e a c t i o n s i s l o n g and i t i s d i f f i c u l t f o r p a t i e n t s on drug t h e r a p y w i t h monoamine o x i d a s e i n h i b i t o r s to f o l l o w t h e s e d i e t a r y r e s t r i c t i o n s . T h i s unf o r t u n a t e f o o d and drug t o x i c i t y r e a c t i o n has l i m i t e d the t h e r a p e u t i c u s e f u l n e s s of these drugs. Enzyme I n a c t i v a t i o n o f C l i n i c a l

Significance

A l a r g e number o f d r u g s , c h e m i c a l s u b s t a n c e s , and some i n g r e d i e n t s o f f o o d s , a r e known t o i n a c t i v a t e cytochrome enzymes. The r e s u l t s a r e s i g n i f i c a n t d u r i n g t h e r a p y w i t h m u l t i p l e drugs i f one o r more o f them i s a s u i c i d e i n a c t i v a t o r o f cytochrome P-450. T h i s s u b j e c t has been s t u d i e d i n t e n s e l y , however, t h e i n f l u e n c e o f d i e t a r y i n g r e d i e n t s on drug a c t i v i t y i n t h i s r e g a r d has n o t r e c e i v e d v e r y much attention. T h i s impaired metabolic d i s p o s i t i o n of a t h e r a p e u t i c drug or f o o d v e r s u s drug i n t e r a c t i o n i s an a r e a f o r f u t u r e r e s e a r c h i n v e s t i g a t i o n t h a t has i m p o r t a n t c l i n i c a l r a m i f i c a t i o n s . These i s sues have been reviewed i n d e t a i l ( 2 9 ) . High F i b e r D i e t s The r e c e n t e n t h u s i a s m f o r h i g h f i b e r f o o d s may c a r r y a s p e c i a l c h a l lenge i n c o n s i d e r i n g food/drug t o x i c i t i e s . Vegetable f i b e r d i e t s have been shown t o r e d u c e t h e t o x i c i t y of some drugs f o r a n i m a l s ( 3 0 ) . Presumably, p h y t a t e s h o l d i n o r g a n i c i o n s i n a c l a t h r a t e m a t r i x t h a t p r e v e n t s a b s o r p t i o n o f the m e t a l from the g u t , o t h e r s u b s t a n c e s , e.g. b i l e a c i d s , may a l s o be bound ( 3 1 ) . The b i o a v a i l a b i l i t y o f i r o n as i n f l u e n c e d by p h y t a t e s i n c e r e a l f o o d s v i a the f o r m a t i o n o f



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insoluble iron phytates is an example of a well known but little understood problem in gastrointestinal physiology and nutrition (32). Magnesium, zinc and tin are covalently bound by fiber and it is possible to produce zinc deficiency in animals by feeding high soybeanprotein diets. On the other hand, potentially toxic substances in foods such as aflatoxins may become less toxic in the presence of fiber in the gut. In experimental animals there is evidence that vegetable fiber is protective against estrogen-induced ovarian and uterine tumors (30). Natural ingredient diets protect rats against carcinogenicinduced mammary tumors (33,34). There is an obvious need to evaluate these potentially useful or harmful effects in man as we come to a better understanding of the effects of changing diets, on drug toxicity and therapeutic usefulness. Summary Changes in man's diet produce marked and often unpredictable effects on drug metabolism. Methods are needed to measure inter-individual and inter-group differences in metabolism of foreign compounds in order to accurately assess dietary influences on drug metabolism and vice versa. Epidemiologic studies of rigorously selected human populations, coupled with the newer sensitive chemical analytical methods will provide the necessary data base for these investigations. Literature Cited 1.

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3. Anderson, K.E., Conney, A.H. & Kappas, A. Nutrtional influences on chemical biotransformations in humans. Nutr Rev, 1983; 40:161-171 3. a Jusko, W.J., et al. Factors affecting theophylline clearances: Age, tobacco, marijuana, cirrosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates and ethanol. J Pharm Sci, 1979; 68:1358-1366 4.

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12. Poland, A. & Kende, A. The genetic expression of aryl hydrocarbon hydroxylase activity: Evidence for a receptor mutation in nonresponsive mice. In Origins of Human Cancer. Cold Spring Harbor Symposium, New York, 1977; 847-967 13. Wattenberg, L.W. & Loub, W.D. Inhibition of polycyclic hydrocarbon-induced neoplasia by naturally-occurring indoles. Cancer Res, 1978; 38:1410-1413 14.

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Sotaniemi, E.A., et al. Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy. Ann Intern Med, 1972; 77:389-394

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RECEIVED

August 28,

1984


Xenobiotic Metabolism: Nutritional Effects - ACS Publications

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