Characterization F. PETER

of human

cytochrome

P450

enzymes

GUENGERICW

Department of Biochemistry and Center Tennessee 3 7232-0146, USA

in Molecular

ABSTRACT Many biochemical approaches have been applied to the human cytochrome P450 enzymes, and more than 20 different gene products have been characterized with regard to their properties and catalytic specifIcities. The complement of the various cytochrome P450 enzymes in a given individual varies markedly, and dramatic differences may be seen in drug metabolism, pharmacological response, and susceptibility to toxic effects. An understanding of the nature of the individual cytochrome P450 enzymes and their regulation should be useful in determining the most suitable animal models, ascertaining risk from chemicals, and in avoiding undesirable drug interactions. Guengerich, F, P. Characterization of human cytochrome P450 enzymes. FASEBJ. 6: 745-748; 1992.

Toxicology,

Vanderbilt

P450

.

drugs

carcinogens

.

School of Medicine,

P450

2C

P450s

were

and

3A gene

purified

families

from

human

(7-9).

Subsequently,

liver

on

EVER

mans there metabolism these

SINCE DRUGS HAVE been administered to huhas been an appreciation of the role of in influencing the pharmacological effects of

agents.

Oxidation

reactions

are

dominant

in

the

metabolism of drugs, and the cytochrome P4502 mixedfunction oxidase system was recognized early as the chief

contributor. By the 1950s variations in rates of drug metabolism were recognized in humans (1). Subsequently, the variations were attributed in part to the presence of different P450 enzymes and the inducibility of some of these (2). Some undesirable drug interactions were attributed to the untoward effects of P450s (3, 4). Studies with experimental animal models have led the way to an understanding information about human orthologs.

knowledge realization

of the P450 these models However,

enzymes, and much has been applicable with the acquisition

about the experimental animal systems that many aspects could be understood

of the to the of

came the only by

studying humans. Over the years, biochemical measurements had been made on human liver surgical samples (for review see ref 5). Much of this information involved levels of

P450, rates

cytochrome plus

rates

b5, and of some

NADPH-cytochrome

typical

P450-dependent

c reduction catalytic ac-

tivities. Kaschnitz and Coon (6) were able to fractionate human liver microsomes into three components enriched in P450, NADPH-P450 reductase, and phospholipid, and demonstrate catalytic activities when these fractions were recombined. At about this time Conney (2) and associates carried out in vivo studies involving enzyme induction which have formed the basis for some of our current understanding of human P450 function.

PURIFICATION

OF

HUMAN

P450s

AND

enzymes

earnest in the late 1970s. The 0892-6638/92/0006-745/$01

from

human

firstP450s

.50. © FASEB

some of partic-

their animal

orthologs

(11). Subse-

with

quently, cDNAs tion by antibodies

were isolated on the basis of their recogniraised against human and animal P450s

(from expression libraries) and cDNAs for animal P450s (12). These isolated DNA probes allowed genomic clones to be isolated and characterized. Today these human P450s are grouped into families on the basis of their primary sequences when they become available (13). The known P450s are listed

in Table

1. In most cases they have been work,

characterized

particularly through

on the

the work

of Gon-

some genomic sequences have been isolated from acid sequence

is un-

available (P4SOMp.1 and MP-2 are proteins in the P450 2C family that appear to differ slightly from the known sequences) (16). Searches for posttranslational modifications (other than heme incorporation) in human P450s have been essentially nonexistent. Two of the P450s are found in mitochondria instead of the endoplasmic reticulum but there may be more

(13,

17).

CATALYTIC

ACTIVITES

OF

HUMAN

P450s

There are many approaches useful in determining which P450s make major contributions to particular catalytic activities.They include the use of selective inhibitors and antibodies in crude (microsomal) preparations, the correlation of individual catalytic activities and P450s in different preparations, and the measurement of catalytic activities with

purified enzymes and in eDNA-derived expression systems. The advantages and disadvantages of each of these techniques have been discussed elsewhere (15). Suffice it to say that the most reliable conclusions are reached when a battery of these approaches is applied. An abbreviated synopsis the catalytic specificities is presented in Table 2. A few major points will be made specificity.First, this matter of selectivity

regarding

of

catalytic

is very important and can influence the probability that an individual will respond to a chemical in a particular way. The P450 enzymes that are devoted to particular steroid hydroxylations tend to have much more limited specificities (e.g., P450s 7, hAl, 11BI, 17, 19, and 21A2). Further, there is probably less variation in the levels of these enzymes among different humans because

of their critical roles in processing

endogenous

cDNA

CLONING Efforts to purify P450

basis

cross-reactivity

liver,and in a few cases the exact amino ALMOST

the

ular catalytic activities (10). Another approach has involved purification of the enzymes on the basis of immunochemical

zalez and his associates (12), and are available. Some of the proteins

steroids

Nashville,

isolated without regard to any catalytic activities, and these first purified enzymes can now be recognized to be in the

basis of eDNA Key Words: cytochrome human studies

University

liver began

in

to be purified were

‘Address correspondence to: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

2Abbreviation:

P450, cytochrome

P450. 745

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TABLE

1. Characterized human P450s P450

Level of characterization

Siteof expression

Primarily extrahepatic Liver Liver (Apparently not expressed) Liver Liver Liver Liver Liver Liver Liver Liver Liver Liver Liver, several extrahepatic

1. 2 3. 4.

lAl IA! 2A6 2A7

eDNA, gene Protein, eDNA, Protein, eDNA eDNA

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

2B6 2C8 2C9 2C10 2C17 2C18 2C19

2D6 2E1

cDNA Protein, (Protein) (Protein) eDNA eDNA eDNA Protein Protein Protein, Protein,

16. 17. 18.

2F1 3A3 3A4

eDNA (Protein) Protein,

eDNA eDNA

Lung Intestine (liver?) Liver, several extrahepatic

19.

3A5

Protein,

eDNA

Liver,

P4SOMP.l

P4SOMp.2

gene

eDNA eDNA eDNA

gene gene

cDNA, eDNA,

tissues

tissues

20. 21.

3A7 4A9

Protein, eDNA cDNA

22. 23. 24.

4B1 7 1 1A1

eDNA eDNA eDNA,

gene

25.

ilBi

cDNA,

gene

several

extrahepatic

tissues Liver (fetal)

Lung Liver Steroidogenic tissues (mitochondria) Steroidogenic tissues

(mitochondria) 26. 11B2 Steroidogenic tissues 27. 17 eDNA, gene tissues Protein, eDNA, gene Steroidogenic 28. 19 Steroidogenic tissues eDNA, gene 29. 21A2 30. For 27 reference, see refs 13-15. Where information is lacking, Liver Protein 31. P450,, the references

are

TABLE

anecdotal

(13).

steroids. Indeed, considerable problems are encountered in those individuals who have genetic P450 21A2 deficiencies (18). Some of the liver microsomal P450s, on the other hand, can tolerate a great deal of diversity in the substrates they accommodate. P450 2E1 and particularly P450 3A4 are unique in this regard. P450 2El oxidizes a variety of lower molecular weight substrates that have few chemical characteristics in common (19). P450 3A4 accommodates a great variety of substrates, even as large as erythromycin and cyclosporin (20). However, its active site should not be viewed as a loose pocket because of the high regioselectivity seen in certain oxidations (e.g., steroids). P450 3A5, which is highly related to P450 3A4, catalyzes some but not all of the same reactions (21). Understanding the structure-activity relationships that underlie the catalytic specificity in these proteins will be a challenging task. Ultimately, physical techniques will need to be brought to bear on the problem. However, it should be kept in mind that recent work with catalytic antibodies has provided elegant evidence for the hypothesis that what determines catalytic specificity is not just the complementarity of the protein to the substrate but the complementarity to the transition state. That is, to quote Kraut (22), catalysis is specificity. Good examples in the P450 field are lacking, but this is an area for future consideration. In many cases there is a conservation of catalytic specificity among the human P450s and their animal orthologs. For instance, this appears to be the general case in the P450 1A1, 1A2, and 2E1 protein families (12, 15). However, apparent discrepancies are sometimes seen because another protein present in the animal tissue may have an unusually high activity toward a particular substrate [e.g., nifedipine (23)]. However, even among very closely related proteins there may be considerable catalytic differences. For instance, rat P450 2Al has testosterone 7a-hydroxylation as a markedly characteristic activity (24) whereas the very similar human P450 2A6 (69% identity) is devoid of this activity (25); both are efficient coumarin 7-hydroxylases. Therefore the catalytic specificity in this protein family seems to be unusually sensitive to small changes, and indeed Lindberg and Negishi (26) have shown that a single change in the sequence of a mouse P450 2A family member can alter its catalytic specificity totally. It also appears that some gene families

2. Some typical P450 substrates and inhibitors Substrates

P450 P450 P450 P450 P450 P450

1AI 1A2 2A6 2B6 2C8, 9, 10 2C18

4S#{176}Mp.i,

Polycyclic

hydrocarbons

Arylamines,

phenacetin,

Coumarin,

Mephenytoin,

MP-2

7,8-Benzoflavone, arylamides

ellipticine

7,8-Benzoflavone

7-ethoxycoumarin

Tolbutamide, Mephenytoin?

P450 2D6

Inhibitors

Sulfaphenazole

hexobarbital hexobarbital

Debrisoquine

and many

related

amines

Quinidine,

some other

alkaloids

P450 2El

Ethanol,

N-nitrosodialkylamines,

vinyl monomers,

Dihydropyridines,

P450 3A3, 4, 5, 7

Disulfiram,

chlorzoxazone

several

steroids,

4-methylpyrazole

Gestodene,

troleandomyein,

naringenin,

cimetidine

cyclosporin, lovastatin, aflatoxins,many

other drugs Cholesterol Cholesterol I 1-Deoxycortisol

P450 7 P450 11AI P450 11BI P450 17 P450 19 P450 21A2 “For referen 746

Vol. 6

Pregnenolone

Testosterone, androstenedione l7-Hydroxyprogesterone Ce,

see

January

refs

Several

drugs

and ligands

14, 15.

1992

The FASEB Journal

GUENGERICH

www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on September 12, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumbe

such as human P450 2C are extremely complex and that catalytic specificity is not well conserved among the members (16).

ENZYME INDUCTION, STIMULATION

INHIBITION,

AND

These three phenomena are all considered together because of the nature of the consequences, even though they are mechanistically quite distinct. Several human P450s are known to be inducible by drugs, usually entities other than the substrates (Table 3). This induction can be an order of magnitude or more. Further, alterations of P450 levels can also be the result of dietary influences and smoking (2). It has been possible to demonstrate the induction of human P450 enzymes in cell culture (27). However, the mechanisms underlying the regulation of P450 genes are complex and will probably be best elucidated in models derived from experimental animals. The suppression of transcription of P450s has been demonstrated in animals, but to date the issue has not been addressed in humans. Some major P450s are not expressed in fetal liver (14, 16, 28). Many inhibitors of P450s are known (Table 2). Some are not particularly selective whereas others are. The significance of these becomes apparent in consideration of drug-drug interactions (vide infra). Further, some P450s such as the aromatase P450 19 are targets in drug therapy (29). Some of the known inhibitors are natural products found in the diet (e.g., naringenin and other flavonoids). The inhibitors may be classified on the basis of their action and include some that act competitively (quinidine, sulfaphenazole), compounds that ligand the heme (cimetidine), compounds whose oxidation products bind the heme (troleandomycin) or adduct the protein (chloramphenicol), and true mechanism-based inactivators (gestodene, disulfiram). Of course, whenever two drugs are administered that compete for the same enzyme site and metabolism is not limited by blood flow, then one can be considered an inhibitor of the other. Direct stimulation of P450 catalytic activities has been demonstrated in human liver microsomal preparations (2). This stimulation may be important for several reasons. 1) In vivo stimulation by such chemicals has been documented in animal models. 2) Many chemicals which show this effect are present in foods. 3) Such stimulation has been demonstrated in human liver microsomes in the activation of carcinogens such as the potent hepatocarcinogen aflatoxin B, (30). 4) Relatively low concentrations of some of the flavones are required to elicit the response. Huang et al. (31) found that the flavones could lower the apparent Km of P450 for NADPH P450 reductase in reconstituted enzyme systems. Schwab et al. (32) found that the Km values of rabbit and human liver

TABLE

3. lnducers of human P450 enzymes”

P450

1A1

P450

lA2

Cigarette Cigarette cruciferous

P450 2C8, 9, 10

smoking smoking,

charbroiled

vegetables barbiturates

Rifampicin, Rifampicin

P450 2E1

Ethanol,

P450 3A4

Rifampicin, barbiturates, troleandomycin

HUMAN

P450s

Q,);

CONCERNS

ABOUT

DRUG

INTERACTIONS

With all of the possibilities involving induction, inhibition, and stimulation, and the many forms of P450, it should not be surprising that adverse drug interactions might result. This is a matter of particular concern in the elderly, where many prescriptions may be encountered simultaneously. Adverse

reactions (and even death) have been experienced

in individuals genetically deficient in P450 2D6 who use certain drugs (35). When phenacetin cannot be oxidized by P450 1A2 in the normal O-deethylation pathway, N-deacetylation can occur and the product phenetidine can lead to methemoglobinemia (36). Induction of P450 3A4 can lead to enhanced oxidation of the oral contraceptive 17cr-ethynylestradiol, and menstruation and unanticipated pregnancies have been experienced in women using rifampicin or barbiturates (4, 37). In a similar manner, the up- or downregulation of P450 3A4 by drugs can influence the metabolism of the immunosuppressive agent cyclosporin and its effects. Prescreening of patients with a noninvasive assay (for enzyme activity) has the potential to facilitate rational therapy (38). Recently the consumption of grapefruit juice has been shown to have a dramatically marked effect in reducing the clearance of dihydropyridine drugs-this effect may be explained by the inhibition of P450 3A4 by the flavonoid naringenin (39). These are just a few examples of the possible complications

terms

that may

ultimately be understood

in

of P450s.

FUTURE

STUDIES

INVOLVING

HUMAN

P4SOS

In the future more basic information about the human P450 enzymes may be expected to become available. Ultimately, a desirable goal is the prediction of catalytic specificity of human P450s toward new drugs and chemicals from structural models. The time required until such an approach becomes feasible cannot be predicted. However, there are noninvasive assays that can be used to estimate how much of a particular P450 is present in an individual (15, 38). Further, in the cases of P450 2D6 and P450 21A2 there is extensive knowledge regarding the genetic analysis of deficiencies. Knowledge about P450s will be of use to physicians and pharmacists in avoiding undesirable drug interactions. Further, the comparison of animal and human P450s may lead

P45OMP.,, MP2

“See refs14, 15.

microsomes for the oxidations of estradiol and progesterone were lowered in the presence of the chemical, and binding studies with a rabbit P450 and a model ligand are consistent with this view (33). The generality of these explanations is not yet clear. What does seem established is that allosteric interactions must be involved, with a separate binding site on the enzyme for the stimulating chemical. We have recently demonstrated that yeast recombinant (human) P450 3A4 oxidizes aflatoxin B1 to both the 8,9-oxide and the 3cr-alcohol (aflatoxin 7,8-benzoflavone stimulates the former reaction and inhibits the latter, thus shifting the metabolism from detoxication to activation (34).

isoniazid(?)

meat,

to rational choices of experimental animal models in the process of safety assessment of drug candidates. Such knowledge may also be useful in improving methods of risk assessment - for instance, knowledge regarding rates and the extent of variation in rates of drug oxidation by humans can be inserted into physiologically based pharmacokinetic models when a critical step has been identified in animal models (40).

747

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This work was supported, in part, by U.S. Public grants CA 44353 and ES 00267.

Health

Service

REFERENCES I. Remmer, H. (1957)The accelerationof evipan oxidationand the demethylationof methylaminopyrine by barbiturates. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 237, 296-307 2. Conney, A. H. (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesisby polycyclicaromatic hydrocarbons: G.H.A. Clowes memorial lecture. Cancer Rev. 42, 4875-4917 3. Kuntzman, R., Mark, L. C., Brand, L.,Jacobson, M., Levin, W., and Conney, A. H. (1966) Metabolism of drugs and carcinogensby human liver enzymes. j Pharmacol. Exp. The’. 152, 151 4. Bolt,H. M., Bolt,M., and Kappus, H. (1977) Interactionof rifampicin treatment

with pharmacokinetics and metabolism

of ethinyloestradiolin

man. Ada Endocrinol. 85, 189-197 5. Distlerath, L. M., and Guengerich, F. P. (1987) Enzymology of human livercyiochromes P-450. In Mammalian Cytochromes P-450, Vol.1 (Guengerich, F. P., ed) pp. 133-198, CRC Press,Boca Raton, Florida 6. Kaschnitz,R. M., and Coon, M. J. (1975)Drug and fattyacidhydroxylationby solubilized human livermicrosomal cytochrome P-450: phospholipidrequirement. Biochem. Pharmacol. 24, 295-297 7. Beaune, P., Dansette, P.; Flinois, J. P., Columelli, S., Mansuy, D., and Leroux, J. P. (1979) Partialpurification of human liver cytochrome P-450. Biochern. Biophys. Rev. Commun. 88, 826-832 8. Kitada, M., and Kamataki, T. (1979)Partialpurification and properties of cytochrome P450 from homogenates of human fetal livers. Biochern. Pharmacol. 28, 793-797 9. Wang, P.,Mason, P.S.,and Guengerich, F.P.(1980)Purification of human liver cytochrome P.450 and comparison to the enzyme isolated from rat liver. Arch. Biochern. Biophys. 199, 206-219 10. Distlerath, L. M., Reilly, P. E. B., Martin, M. V., Davis, C. G., Wilkinson, G. R., and Guengerich, E P. (1985) Purification and characterization of the human livercytochromes P-450 involvedin debrisoquine 4-hydroxylation and phenacetin 0-deethylation,two prototypes for genetic polymorphism in oxidative drug metabolism.J. Biol. C/tern. 260, 905 7-906 7 11. Watkins, P. B., Wrighton, S. A., Maurel, P.,Schuetz, E. C., Mendez. Picon,G., Parker,G. A., and Guzelian, P.S. (1985)Identification of an inducible form of cytochrome P-450 inhuman liver. Proc. Nati. Acad. Sci. USA 82, 6310-6314 12. Gonzalez, F. J. (1989) The molecular biology of cytochrome P450s. Pharrnacol. Rev. 40, 243-288 13. Nebert, D. W., Nelson, D. R., Coon, M. 3., Estabrook, R. W., Feyereisen, R., Fujii-Kuriyama, Y., Gonzalez, F. J., Guengerich, F. P., Gunsalus, 1. C., Johnson, E. F., Loper, J. C., Sato, R., Waterman, M. R., and Waxman, D. 3. (1991)The P450 superfamily: update on new sequences,gene mapping, and recommended nomenclature.DNA Cell Biol. 10, 1-14 14. Guengerich, F. P. (1989) Characterizationof human microsomal cytochrome P-450 enzymes. Annu. Rev. Pharmacol. Toxicol. 29, 241-264 15. Guengerich, F. P.,and Shimada, 11(1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. ‘hern. Rev. Toxicol. 4, 391-407 16. Srivastava, P. K., Yun, C-H., Beaune, P. H., Ged, C., and Guengerich, F.P.(1991)Separationof human livertolbutaminehydroxylaseand (S)mephenytoin 4’-hydroxylase cytochrome P-450 enzymes. Mo!. Phar. macol. 40, 69-79 17. Shayiq, R. M., and Avadhani, N. G. (1989) Purification and characterization of a hepatic mitochondrial cytochrome P-450 active in aflatoxin B metabolism. Biochemistry 28, 7546-7554 18. Higashi, Y., Hiromasa, T., Tanae, A., Miki, T., Nakura, J., Kondo, T., Ohura, T., Ogawa, E., Nakayama, K., and Fujii-Kuriyama,Y. (1991)

Effects of individual mutations

in the P-450 (C21) pseudogene on the

P-450 (C2l) activity and their distribution in the patient genomes of congenitalsteroid21-hydroxylasedeficiency. j Biochern. (Tokyo) 109,

638-644 19. Guengerich, F. P., Kim, D-H., and Iwasaki, M. (1991) Role of human cytochrome P-450 IIEI in the oxidationof severallow molecularweight

cancer suspects.Chern. Rev. lbxicol. 4, 168-179

20. Brian, W. R., Srivastava, P. K., Umbenhauer, D. R., Lloyd, R. S., and Guengerich, F. P. (1989) Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Sacc/iaromyce.s cerevisiae. Biochemistry 28, 4993-4999 21. Wrighton, S. A., Brian, W. R., Sari, M. A., Iwasaki, M., Guengerich, F. P., Raucy, J. L., Molowa, D. T., and Vandenbranden, M. (1990) Studies on the expressionand metabolic capabilities of human liver cytochrome P45OIIIA5 (HLp3). Mol. Pharmacol. 38, 207-213 22. Kraut, J. (1988) How do enzymes work? Science 242, 533-539 23. Guengerich, F. P., Martin, M. V., Beaune, P. H., Kremers, P., Wolff, T., and Waxman, D. J. (1986) Characterization of ratand human liver microsomal cytochrome P-450 forms involvedin nifedipineoxidation, a prototypeforgeneticpolymorphism in oxidativedrug metabolism.j Biol: Chern. 261, 5051-5060 24. Levin, W., Thomas, P. E., Ryan, D. E., and Wood, A. W. (1987)Isozyme specificityof testosterone 7a-hydroxylation in rat hepatic microsomes: iscytochrome P-450a the sole catalyst? Arch. Biochem. Biophys. 258, 630-635 25. Yun, C-H., Shimada,

T., and Guengerich,

F. P. (1991) Purificationand

characterization of human livermicrosomal cytochrome P-450 2A6. Mol. Pharrnacol. 40, 679-685 26. Lindberg, R. L. P., and Negishi, M. (1989) Alteration of mouse cytochrome P45Ocoh substrate specificity by mutation of a single aminoacid residue. Nature (London) 339, 632-634 27. Morel, P.,Beaune, P. H., Ratanasavanh, D., Flinois, 3-P.,Yang, C-S., Guengerich, F. P.,and Guillouzo,A. (1990)Expressionof cytochrome P-450 enzymes in culturedhuman hepatocytes.Eur. j Biochern. 191, 437 -444

28. Kitada, M., Kamataki, T., Itahashi,K., Rikihisa,T.,and Kanakubo, Y. (1987) Significance of cytochrorne P-450 (P.450 HFLa) of human fetal livers in the steroid and drug oxidations. Biochern. Pharinacol. 36, 453-456

29. Cole, P. A., and Robinson, C. H. (1990)Mechanism and inhibitionof cytochrorne P.450 aromatase. j Med. Chem. 33, 2933-2942 30. Shimada, T., and Guengerich, F. P. (1989) Evidence for cytochrome P45ONF, the nifedipine oxidase, being the principal enzyme involved

in the bioactivation of aflatoxinsin human USA 86, 462-465 31. Huang,

M.

T., Johnson,

liver.Proc. Nail. Acad. Sci.

P.. F., Muller-Eberhard,

U.,

Koop,

D. R., Coon, M. J., and Conney, A. H. (1981)Specificity in the activationand inhibitionby flavonoidsof benzo[a]pyrene hydroxylationby cytochrome P-450 isozymes from rabbit liver microsomes.j Biol. C/tern. 256, 10897-10901 32. Schwab,

G.

E., Raucy,

J. L.,

and Johnson,

E. P. (1988) Modulation

of

rabbitand human hepaticcytochrome P.450-catalyzedsteroidhydroxylations by a-naphthofiavone. Mol. PharmacoL 33, 493-499 33. Johnson, E. F.,Schwab, G. E.,and Vickery,L. E. (1988) Positive effectors of the binding of an active site-directed amino steroid to rabbit cytochrome P-450 3c.J. Biol. Chern. 263, 17672-17677 34. Guengerich, F.P.,Shimada, T.,Raney, K. D.,Yun, C-H., Meyer, D. J., Ketterer, B., Harris, T. M., Groopman,J. D., and Kadlubar, F. F. (1992) Elucidation of catalytic specificities of human cytochrome P-450 and glutathione S-transferase enzymes and relevance to molecular epidemiology studies. Environ. Health Perspect. In press 35. Sloan, P., Mahgoub, A., Lancaster, R., Idle, J. R., and Smith, R. L. (1978) Polymorphism of carbon oxidation of drugs and clinical implications. Brig. Med. j 2, 655-657 36. Klehr, H., Eyer, P., and Schafer, W. (1987) Formation of 4-ethoxy-4’-nitrosodiphenylamine in the reactionof the phenacetin metabolite 4-nitrosophenetol with glutathione. Biol. Chern. Hoppe-Seyler

368, 895-902 37. Guengerich, F.P.(1990)Metabolism of l7a-ethynylestradiol inhumans. Lfe Sci. 47, 1981-1988 38. Watkins, P. B.,Hamilton, T. A., Annesley,T. M., Ellis, C. N., Kolars, J. C., and Voorhees, J. J. (1990) The erythromycin breath test as a predictor of cyclosporine blood levels. Clin. Pharmacol. The,’. 48, 120-129 39. Cuengerich, F. P., and Kim, D-H. (1990) In vitro inhibitionof dihydropyridine

oxidation and

aflatoxin B, activation in human

liver

microsomes by naringenin and other flavonoids.Carcinogenesis 11, 22 75-22 79 40. Reitz, R. H., Mendrala, A., and Guengerich, F. P. (1989) In vitro metabolism of methylene chloridein human and animal tissues: use in physiologically-based pharmacokinetic models. Toxicol. Appi. Pharmacol.

97, 230-246

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Characterization of human cytochrome P450 enzymes.

Many biochemical approaches have been applied to the human cytochrome P450 enzymes, and more than 20 different gene products have been characterized w...
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