Xenobiotic Metabolism: Nutritional Effects - American Chemical Society

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Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on February 28, 2018 | https://pubs.acs.org Publication Date: May 6, 1985 | doi: 10.1021/bk-1985-0277.ch012

Modulation of Benzo[a]pyrene Metabolism by Dietary Sulfur Amino Acids EDWARD L. WHEELER, DANIEL E. SCHWASS, LADELL CRAWFORD, and DAVID L. BERRY Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Albany, CA 94710 Nutritional and nutritional status markedly influence xenobiotic metabolism in laboratory animals. Microsomes were prepared from the livers of rats which had been fed chow or modified AIN-76 diets with or without oxidized or unoxidized sulfur amino acids for 7 days. The pattern of benzo(a)pyrene (BaP) metabolites formed by each microsomal preparation in the presence of a NADPH-generating system was determined using high performance liquid chromatography (HPLC). The results indicate that oxidized sulfur amino acids induce different forms of cytochromes P-450 in rat liver which are reflected by different BaP metabolic profiles. It is well established that diet can play a part in the cancer process (1,2,3). Food-borne chemicals, either additives or "natural", can induce profound changes in monooxygenase systems of the liver and gastrointestional tract, especially (but not exclusively), in the various cytochrome P-450 isoenzymes responsible for the initial oxidation steps in xenobiotic metabolism (4,5,6,7,8). Constitutive forms of cytochrome P-450 may be repressed while other forms are induced. It is the induced forms, particularly cytochrome P-448 or aryl hydrocarbon hydroxylase, that are primarily responsible for converting aromatic hydrocarbons such as benzo(a)pyrene (BaP), a compound prevalent in fried and broiled meats and cigarette smoke, into highly carcinogenic metabolites (9,10,11). In addition to cytochrome P-450 induction, other diet induced metabolic effects are likely to be involved in carcinogenesis. High temperature processing or long-term storage of foods with attendant exposure to oxygen can lead to the formation of lipid peroxides and oxidized sulfur amino acids in the food. The partially oxidized S-amino acids cystine monoxide (CMO) and methionine sulfoxide (MSO) are nutritionally available, but require in vivo conversion to the reduced amino acids at the This chapter not subject to U.S. copyright. Published 1985 American Chemical Society

Finley and Schwass; Xenobiotic Metabolism: Nutritional Effects ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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expense o f NADH and NADPH ( 1 1 , 12, 1 3 ) . L i p i d p e r o x i d e s promote the oxidation of S-amino acids and many other cellular components, and a r e d e t o x i f i e d i n v i v o a t t h e expense o f reduced glutathione (GSH) (14,15). This information leads to the hypothesis that d i v e r s i o n of c e l l u l a r reducing equivalents to the r e d u c t i o n o f o x i d i z e d d i e t a r y p r o t e i n o r l i p i d may e f f e c t a n u t r i t i o n a l s t r e s s on t h e a n i m a l t h a t d e t r a c t s from o r a l t e r s i t s a b i l i t y t o m e t a b o l i z e x e n o b i o t i c s s u c h as BaP v i a NADPH dependent cytochromes P-450 r e a c t i o n s . This preliminary work demonstrates that dietary oxidized S-amino acids do l e a d t o a l t e r e d BaP m e t a b o l i s m by liver microsomes under i n v i t r o c o n d i t i o n s o f e x c e s s NADPH and 0^. M a t e r i a l s and Methods Male Sprague Dawley r a t s , seven days p o s t w e a n l i n g ( B a n t i n and Kingman, I n c . , Fremont, CA) were f e d p e l l e t e d r o d e n t chow (5001, Ralston Purina Co., S t . L o u i s , MO) o r m o d i f i e d AIN-76 d i e t s (BioServ, I n c . , Frenchtown, NJ) w i t h o r w i t h o u t added s u l f u r amino a c i d s . Chow, d i e t s , and water were s u p p l i e d t o t h e r a t s ad l i b i t u m . The AIN-76 d i e t (16) was m o d i f i e d t o c o n t a i n 12% c a s e i n ( n o r m a l l y 2 0 % c a s e i n ) , and t h e weight d i f f e r e n c e made up with cornstarch. The normal m e t h i o n i n e supplement was n o t included. The cornstarch and s u c r o s e portions were held s e p a r a t e l y from t h e c a s e i n / v i t a m i n / m i n e r a l (CVM) m i x t u r e f o r t h e p u r p o s e o f m i x i n g amino a c i d s w i t h t h e c o r n s t a r c h and s u c r o s e (CsS). M e t h i o n i n e (MET), m e t h i o n i n e s u l f o x i d e (MSO) and c y s t e i n e s u l f i n i c a c i d (CSA) were o b t a i n e d from Sigma C h e m i c a l Co., S t . L o u i s , MO. C y s t e i n e monoxide (CMO) was p r e p a r e d by t h e method o f Savige e t a l . , (17). Amino a c i d a d d i t i o n s t o t h e d i e t s ( i f any) were a c c o m p l i s h e d by p r o g r e s s i v e l y m i x i n g s m a l l amounts o f t h e amino a c i d and CsS i n a m o r t a r u n t i l a l l o f t h e amino a c i d was added. The CsS/amino a c i d m i x t u r e was t r a n s f e r r e d t o a Hobart N-50 m i x e r ( T r o y , OH) and t h e r e m a i n d e r o f t h e CsS and CVM were added and mixed. The l e v e l o f s u p p l e m e n t a t i o n o f s u l f u r amino a c i d s t o t h e d i e t s was e q u i v a l e n t t o 3.63 mmoles amino a c i d / 1 0 0 gm d i e t . S i x animals were h e l d on e a c h d i e t f o r seven days b e f o r e they were s a c r i f i c e d by c e r v i c a l d i s l o c a t i o n . The l i v e r s were immediately removed, p o o l e d w i t h o t h e r s i n t h e group, weighed, minced and homogenized i n 3 x w/v b u f f e r (pH 7.2, 0.05 M p o t a s s i u m phosphate, 0.025 M p o t a s s i u m c h l o r i d e , 0.0025 M magnesium c h l o r i d e , 0 . 2 5 M s u c r o s e ) . Microsomes were p r e p a r e d by t h e method o f M a z e l (18) as m o d i f i e d by Wheeler ( 1 9 ) , and cytochrome P-450 l e v e l s d e t e r m i n e d by t h e method o f Omura and Sato u s i n g an a b s o r p t i v i t y c o n s t a n t o f 91 mM" cm~ . P r o t e i n was d e t e r m i n e d by t h e method o f Lowry u s i n g b o v i n e serum a l b u m i n ( F r a c t i o n V, Sigma C h e m i c a l Co., S t . L o u i s , MO) as a s t a n d a r d . A P e r k i n - E l m e r Model 320 (Norwalk, CT) was u s e d f o r s p e c t r o p h o t o m e t r i c measurements. 1

1

BaP (Sigma C h e m i c a l Co., S t . L o u i s , MO) was o x i d i z e d a t 37°C under a b l a n k e t of 0 by m i c r o s o m a l cytochrome P-450 i n a 2

reaction mixture containing 0.03 M Mg glucose-6-phosphate (Sigma), 1 mg NADPH (P-L Milwaulkee, WI), 8 units glucose-6-phosphate

, 30 mg Biochemicals, dehydrogenase



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(Sigma) and 1 nmole cytochrome P-A50. These components were diluted to a total volume of 2.0 ml with 0.05 potassium p h o s p h a t e , pH 7.4. The r e a c t i o n was s t a r t e d by a d d i n g 60 nmole BaP (15 i x l o f a 1 mg/ml s o l u t i o n i n a c e t o n i t r i l e ) . A f t e r 15 min, the m i x t u r e was s a t u r a t e d w i t h sodium c h l o r i d e and e x t r a c t e d t h r e e t i m e s w i t h 4.0 ml c o l d e t h y l a c e t a t e : acetone ( 2 . 5 : 1 ) . The aqueous and o r g a n i c l a y e r s were s e p a r a t e d by c e n t r i f u g a t i o n and the combined o r g a n i c f r a c t i o n s e v a p o r a t e d under a stream of nitrogen. The r e s i d u e was d i s s o l v e d i n 300 u l methanol and 25 u l o f t h i s s o l u t i o n was s e p a r a t e d u s i n g a S p e c t r a - P h y s i c s SP8700 l i q u i d chromatograph ( S a n t a C l a r a , CA) f i t t e d w i t h a 25 cm., 5 m i c r o n C-18 column ( R a i n i n I n s t . Co., Woburn, MA) and equipped with a variable wavelength detector (Spectro-monitor III, L a b o r a t o r y Data C o n t r o l , R i v i e r a Beach, FL) and a f l u o r e s c e n c e d e t e c t o r (Model 420-C, Waters A s s o c . , I n c . , M i l f o r d , MA). Samples were n o t f i l t e r e d b e f o r e i n j e c t i o n because c e r t a i n m e t a b o l i t e s , e s p e c i a l l y the d i o l s and an unknown compound e l u t i n g j u s t b e f o r e t h e 7,8- d i o l , absorbed t o b o t h n y l o n 66 and PTFE f i l t e r s . A methanol-water r a t e g r a d i e n t was d e v e l o p e d w h i c h s e p a r a t e d t h e s t a n d a r d BaP m e t a b o l i t e s ( r e c e i v e d from t h e N a t i o n a l C a n c e r I n s t i t u t e Chemical Carcinogen Reference Standard R e p o s i t o r y , a f u n c t i o n o f the D i v i s i o n o f C a n c e r Cause and P r e v e n t i o n , NCI, Bethesda, MD 20205) and r e - e q u i l i b r a t e d the column i n about 30 min. A diagram o f the g r a d i e n t i s shown i n F i g u r e 1. A mixture o f BaP m e t a b o l i t e s t a n d a r d s was s e p a r a t e d u s i n g t h i s system and eluted in the following order: 7,8-diol-9,10-epoxide and 9,10-diol (overlapping peaks); 4 , 5 - d i o l ; 7 , 8 - d i o l ; 1,6-dione; 3,6-dione; 4,5-epoxide; 6,12d i o n e ; 9-hydroxy; 6-hydroxy and 1-hydroxy ( o v e r l a p p i n g p e a k s ) ; 3-hydroxy; and unchanged BaP. The 4 , 5 - d i o l and 4,5-epoxide were q u a n t i f i e d by UV absorbance a t 255 nm, and the o t h e r compounds by f l u o r e s c e n c e i n t e n s i t y a t 450 nm. M e t a b o l i t e s from e x t r a c t e d r e a c t i o n m i x t u r e s were i d e n t i f i e d and quantified by comparison with standard mixtures of known concentration. Organic s o l v e n t s used f o r l i q u i d chromatography were from OmniSolv (MCB M a n u f a c t u r i n g Chemists, I n c . , C i n c i n n a t i , OH) and w a t e r was d i s t i l l e d , d e i o n i z e d and f i l t e r e d t h r o u g h a 0.2u n y l o n 66 membrane ( R a i n i n ) . A l l c h e m i c a l s w i t h no s o u r c e identified were o f r e a g e n t grade. RESULTS AND

DISCUSSION

Microsomes from rats fed diets deficient i n methionine and c o n t a i n i n g added m e t h i o n i n e have the l o w e s t l e v e l s o f cytochrome P-450, t h e m o d i f i e d AIN-76 ( m e t h i o n i n e d e f i c i e n t ) d i e t a p p a r e n t l y c a u s i n g a d e p r e s s i o n i n the l e v e l o f cytochrome P-450 compared t o t h e c o n t r o l (AIN/MET) d i e t ( T a b l e I ) . The o t h e r d i e t s i n d u c e d cytochrome P-450 i n the l i v e r s , i n c l u d i n g t h e chow d i e t which i n d u c e d cytochrome P-450 a p p r o x i m a t e l y t w i c e as much as any o f the o t h e r d i e t s . I n a d d i t i o n , chow and AIN/CSA s h i f t e d the cytochrome P-450-CO reduced d i f f e r e n c e - s p e c t r a peak t o 449.3 nm, indicating that a s i g n i f i c a n t amount o f cytochrome P-448 was i n d u c e d by t h e s e d i e t s . I n t h e case o f the r o d e n t chow, o x i d i z e d lipids as well as oxidized sulfur amino acids could be


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J9.5 MIN

22.5 MIN

TIME (Min)

Fig. 1. Solvent program (methanol-H 0) for HPLC separation 2

of BaP metabolites at 21°C.

TABLE I DIFFERENCES IN CYTOCHROMES P-450 INDUCTION AS A FUNCTION OF DIET

DIET

REDUCED CO ABS MAX (NM)

uM P-450

CHOW *AIN **AIN/MET AIN/MSO AIN/CMO AIN/CSA

449.3 450 450 450 450 449.3

5.30 1.25 1.60 2.34 3.00 2.31

NMOLE P-450 PER MG P 0.64 0.31 0.38 0.40 0.45 0.40

*The m o d i f i e d AIN-76 d i e t d e s c r i b e d under "Methods" **AIN/MET as t h e " c o n t r o l " d i e t throughout

t h e work



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r e s p o n s i b l e f o r t h e i n d u c t i o n and peak s h i f t . One i m p l i c a t i o n o f this result i s that i n v e s t i g a t o r s studying cytochrome P-450 i n d u c t i o n s h o u l d be wary o f u s i n g commercial chow a s a c o n t r o l diet. A t y p i c a l f l u o r e s c e n c e chromatogram o f BaP m e t a b o l i t e s i s shown i n F i g u r e 2. The n o n - f l u o r e s c i n g ( t h u s n o t shown) 4 , 5 - d i o l e l u t e s a t 10.2 min between t h e unknown compound (C) and t h e 7 , 8 - d i o l (D). I f any 6-hydroxy BaP had been found, i t would have eluted just before t h e 1-hydroxy peak (K). Two of the m e t a b o l i t e s t h a t a r e p a r t i c u l a r l y i n t e r e s t i n g a r e t h e t e t r o l s (A) and the u n i d e n t i f i e d peak (C), i n that there a r e major d i f f e r e n c e s among t h e v a r i o u s microsomes i n t h e q u a n t i t i e s o f t h e s e compounds w h i c h were formed ( T a b l e I I ) . The t e t r o l s , which arise from t h e u n s t a b l e , h i g h l y c a r c i n o g e n i c 7,8 d i o l , 9,10 epoxide ( 2 0 ) , were c o n s p i c u o u s l y absent from r e a c t i o n m i x t u r e s from t h e AIN/MET and AIN/MSO microsomes. The t e t r o l s were always p r e s e n t i n t h e o t h e r f o u r c a s e s , however, and were h i g h e s t from t h e chow microsome r e a c t i o n m i x t u r e s . The i m p l i c a t i o n i s t h a t dietary stress such as may be i n c u r r e d by t h e p r e s e n c e o f o x i d i z e d l i p i d s (chow) o r t h e absence o f e s s e n t i a l amino a c i d s ( m e t h i o n i n e ) , may p l a y a r o l e i n t h e oncogenic p r o c e s s by t h e induction of d i f f e r e n t forms o f cytochrome P-450 and/or t h e s u p r e s s i o n o f c o n s t i t u t i v e forms. The unknown peak (C) i n F i g u r e 1 may a l s o p r o v e t o be i m p o r t a n t . The BaP m e t a b o l i s m c a t a l y z e d by t h e c o n t r o l (AIN/MET) microsomes y i e l d e d no more than a t r a c e o f peak C, w h i l e t h e d i e t n o t supplemented w i t h m e t h i o n i n e (AIN) and t h e c y s t e i n e s u l f i n i c a c i d - s u p p l e m e n t e d d i e t (AIN/CSA) had measurable amounts. L e v e l s o f peak C were h i g h e s t i n t h e c a s e s o f t h e o t h e r t h r e e d i e t s (chow, AIN/MSO and AIN/CMO), e s p e c i a l l y f o r AIN/MSO and AIN/CMO. I n t h i s c a s e , t h e d i e t a r y s t r e s s may have a r i s e n from t h e need f o r CMO and MSO t o be reduced back t o t h e f r e e amino a c i d forms f o r u s e by t h e r a t . T h i s unknown compound may have been o v e r l o o k e d by o t h e r i n v e s t i g a t o r s u s i n g UV a b s o r p t i o n f o r t h e d e t e c t i o n o f m e t a b o l i t e s because i t has a v e r y low a b s o r p t i v i t y c o n s t a n t a t 255 nm. and i s u n s t a b l e . Most o f the fluorescence at this retention time disappears after o v e r n i g h t sample s t o r a g e a t -10°C. The microsomes from t h e CMO-fed rats produced t h e most s t r i k i n g d i f f e r e n c e s i n m e t a b o l i c p r o f i l e compared t o t h e c o n t r o l microsomes. The d a t a shown i n T a b l e I I I and F i g 3 ( f o r c l a r i t y ) demonstrate that microsomes from animals f e d the cysteine monoxide d i e t (AIN/CMO) a r e f a r more e f f i c i e n t a t m e t a b o l i z i n g BaP (more BaP o x i d i z e d p e r mole cytochrome P-450/unit time) t h a n a r e microsomes from r a t s f e d t h e c o n t r o l d i e t (AIN/MET). Lower r e c o v e r y o f BaP and m e t a b o l i t e s was o b t a i n e d from t h e microsomes o f t h e AIN/CMO-fed r a t s compared t o t h e AIN/M-fed r a t s (87 t o 91%) and a c o n t r o l r u n c o n t a i n i n g no NADPH ( 9 4 % r e c o v e r y ) . This r e s u l t i s p r o b a b l y due t o t h e f a c t t h a t t h e t e t r o l s and t h e unknown m e t a b o l i t e , b o t h p r e s e n t i n much g r e a t e r amounts i n t h e CMO c a s e than i n t h e MET ( c o n t r o l ) c a s e , a r e n o t q u a n t i f i a b l e , and thus have n o t been considered i n the calculations. Microsomes from t h e chow-fed rats behaved similarly to the microsomes from AIN/CMO-fed r a t s , w h i l e t h e o t h e r c a s e s showed i n t e r m e d i a t e v a l u e s o f r e c o v e r y ( d a t a n o t shown). I n every case,



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UJ O Z UJ o (/) UJ OT

O ZD

10

30

20

MINUTES Figure 2. Fluorescence chromatogram of BaP metabolites formed by microsomes from l i v e r s of rats fed the diets described i n "Methods". Key: A, various t e t r o l s ; B, 9,10 d i h y d r o d i o l ; C, unknown; D, 7,8 dihydrodiol; E, unkown; F, extraneous microsomal m a t e r i a l ; G, 1,6 quinone; H, 3,6 quinone; I, 6,12 quinone; J , 9 hydroxy; K, 1 hydroxy; L, 3 hydroxy; M, unchanged BaP.

TABLE I I R e l a t i v e D i f f e r e n c e s i n t h e Amounts o f T e t r o l s and a M a j o r Unknown M e t a b o l i t e Formed by Microsomes from L i v e r s o f Rats Fed Various D i e t s

Total* Tetrols Unkown* Peak D

CHOW

AIM

AIN/M

AIN/MSTO

3700

2150

trace

trace

8865

1483

trace

10,170

*Arbitrary Integration

AIN/CMO

AIN/CSA

3000

3500

10,070

2860

units


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TABLE I I I


D i e t a r y I n f l u e n c e on M i c r o s o m a l BaP M e t a b o l i s m Diet AIN/M

METABOLITE OF BaP

nmoles

CONTROL*

AIN/CMO

% of T o t a l

nmoles % o f T o t a l

9,10

Diol

.039

0.84

.065

1.50

4,5

Diol

.048

1.06

.050

1.16

7,8

Diol

.007

0.16

.016

0.37

1,6

Quinone

.053

1.18

.093

2.15

3,6

Quinone

.071

1.57

.169

3.91

9-OH

.013

0.30

.021

0.49

1-OH

.015

0.33

.029

0.67

3-OH

.152

3.37

.251

5.80

Parent

BaP

Totals % Recovery**

4.11

4.51 91

91.1

84

3.63

4.32

4.66 94

87

*No NADPH added t o t h e o r i g i n a l r e a c t i o n

4.66

mixture.

**nmoles o f unchanged BaP p l u s a l l m e t a b o l i t e s = 4 . 9 6 nmoles i f 100% r e c o v e r y


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the 1,6

major m e t a b o l i t e was 3-OH BaP, f o l l o w e d by the 3,6 and the quinones. The r e s u l t s depicted i n f i g u r e s 4, 5, and 6 p e r h a p s b e s t demonstrate the differences in BaP metabolism among the microsomes from r a t s f e d the v a r i o u s d i e t s . The nmoles o f the l i s t e d metabolites i n each c a s e a r e compared w i t h the nmoles of metabolites found f o r the AIN/MET c o n t r o l d i e t , which were arbitrarily assigned a value of 1.0. The most notable d i f f e r e n c e s appear t o be: CSA and CMO supplemented d i e t s l e d t o more o f a l l the m e t a b o l i t e s than the MET supplemented d i e t , as d i d MSO and chow t o a l e s s e r e x t e n t ; and the h i g h l y r e a c t i v e (on a c e l l u l a r l e v e l ) 7, 8 - d i o l and 1,6 and 3,6 q u i n o n e s were found a t much h i g h e r l e v e l s i n the CSA and CMO c a s e s (and chow a l s o ) t h a n i n the MET c a s e . The v a r i a t i o n among the v a r i o u s d i e t s i n t h e amounts o f the p r i m a r y m e t a b o l i c p r o d u c t 3-OH BaP formed ( F i g u r e 6) i s not l a r g e compared t o v a r i a t i o n s i n the other s e c o n d a r y p r o d u c t s s u c h as the 7,8 diol (Figure 4 ) , quinones ( F i g u r e 5 ) , and t e t r o l s (shown i n T a b l e I I ) . T h e r e f o r e i t i s the s e c o n d a r y o x i d a t i o n r e a c t i o n s t h a t a r e s i g n i f i c a n t l y a l t e r e d by d i e t s c o n t a i n i n g o x i d i z e d S-amino a c i d s . The major p o i n t shown by this preliminary study i s that v a r i o u s o x i d i z e d s u l f u r amino a c i d s i n the d i e t i n d u c e d i f f e r e n t forms o f cytochrome P-450 i n r a t l i v e r s which, i n e q u i m o l a r amounts, have d i f f e r e n t e f f i c i e n c i e s and yield different BaP metabolite p r o f i l e s i n v i t r o . An i l l a t i o n t h a t may be drawn from t h e s e r e s u l t s i s t h a t e a t i n g p a r t i a l l y o x i d i z e d f o o d s may l e a d t o c a r c i n o g e n a c t i v a t i o n v i a the d i e t a r y i n d u c t i o n o r a l t e r a t i o n o f v a r i o u s forms and r e l a t i v e q u a n t i t i e s o f cytochromes P-450 and related activities.



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9,10-diol

4,5-diol

159

7,8-diol

F i g u r e 4. R e l a t i v e amounts of BaP m e t a b o l i t e s , 9 , 1 0 - d i o l , 4 , 5 - d i o l , and 7 , 8 - d i o l , formed by the f i v e t e s t d i e t s n o r m a l i z e d to the c o n t r o l AIN/MET d i e t .

F i g u r e 5. R e l a t i v e amounts of BaP m e t a b o l i t e s , 1,6-quinone and 3,6-quinone, formed by the f i v e t e s t d i e t s n o r m a l i z e d t o the c o n t r o l AIN/MET d i e t .



160

XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS

9-OH

1-OH

3-OH

Figure 6. Relative amounts of BaP metabolites, 9-OH, 1-OH, and 3-OH, formed by the five test diets normalized to the control AIN/MET diet.

LITERATURE CITED 1. Ames, Bruce N., Science. 1983; 221: 1256. 2. Newell, Guy R., Cancer. 1983; 51: 2420. 3. Palmer, Sushma and Bakshi, Kulbir, J. Natl Cancer Inst.. 1983; 70: 1153. 4. Pascoe, Gary A., Sakai-Wong, Joanne, Soliven, Eva and Correia, Almira M., Biochem. Pharma.. 1983, 32: 3207. 5. Hendrich, S. and Bjeldanes, L.F., Fd. Chem. Toxicol.. 1983; 21:479. 6. Wattenberg, Lee W., Loub, William D., Lam, Luke K., and Speier, Jennine L., Fed. Proc., 1976; 35: 1327. 7. Gelboin, Harry V., Physiol. Rev., 1980; 60:1107. 8. Hennig, Eva E., Dobrzanski, Krzysztof K., Sawicki, Jozef T., Mojska, Hanna and Kujawa, Marek, Carcinogenesis, 1983; 4:1243. 9. Robertson, Iain G.C., Zeiger, Errol, and Goldstein, Joyce A., Carcinogenesis, 1983; 4: 93. 10. Parke, Dennis V., Biochem Soc. Trans. 1983; 11:457. 11. Levin, W., Wood, A.W., Lu, A.Y.H., Ryan, D., West, S., Conney, A.H., Thakker, D.R., Yagi, H., and Jerina, D.M., A.C.S. Symp. Series. 1977; 44:99. 12. Aymard, C., Seyer, L., and Cheftel, J.C., Agric. Biol. Chem., 1979; 43:1869. 13. Crawford, L., Finley, J.W., and Robbins, K., Nutr. Reports International 1984; 29:791



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14. Plummet, J.L., Smith, B.R., Sies, H., and Bend, J.R., Methods in Enzymology. 1981; 77:50. 15. Sies, H., Akerboom, T.P.M., and Cadenas, E., Biochem. Soc. Trans., 1982; 10;79. 16. Second Report of Ad Hoc Committee on Standards for Nutritional Studies. J. Nutrition. 1980; 110:1726. 17. Savige, W.E., Eager, J., Maclaren, J.A., Rexburgh, C.M., Tetrahedron Letters. 1964; 44, 3389. 18. Mazel, P., in "Fundamentals of Drug Metabolism and Drug Disposition", B.N., LaDu, G.H., Mandel, E.L. Way, eds., Williams and Wilkins Co., Baltimore, MD., 1972; 546. 19. Wheeler, E.L., Biochem. Biophys. Res. Comm., 1983; 110:646. 20. Phillips, D.H., Sims, Peter, in "Chemical Carcinogens and DNA", Philip L. Grover, ed., CRC Press, Inc., Boca Raton, Fla., 1979. RECEIVED

October 8,

1984


Xenobiotic Metabolism: Nutritional Effects - American Chemical Society

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