Skip to main content

Advertisement

SpringerLink
Log in

Cytochrome P450 3A and their regulation

  • Review
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

CYP3A isozymes collectively comprise the largest portion of the liver and small intestinal CYP protein and they are involved in the metabolism of 45–60% of all currently used drugs. In addition to drugs, CYP3A isozymes metabolise a variety of other compounds including steroid hormones, toxins and carcinogens. It is also well known that the hepatic expression and activity of CYP3A isozymes varies from individual to individual. The involvement of this variability in harmful interactions frequently encountered in development and application of drugs that are CYP3A substrates is well documented. It has also been postulated that variable CYP3A expression could affect an individual’s predisposition to cancers caused by environmental carcinogens that are metabolised by CYP3A. The elucidation of factors controlling an individual’s CYP3A activity could permit personalised dose adjustments in therapies with its substrates and may also possibly lead to the identification of sub-populations at increased risk for several common cancers. However, until recently, the development of markers predictive for the individual CYP3A expression has been slower than for other drug metabolising enzymes. Here we summarise the current status of our understanding of the genetics and regulation of the expression of CYP3A, including the recently described markers of the CYP3A5 and CYP3A7 polymorphisms. These latter markers are expected to speed up the development of activity probes for the individual CYP3A isozymes and to aid in our understanding of their individual functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ahsan CH, Renwick AG, Macklin B, Challenor VF, Waller DG, George CF (1991) Ethnic differences in the pharmacokinetics of oral nifedipine. Br J Clin Pharmacol 31:399–403

    CAS  PubMed  Google Scholar 

  • Amirimani B, Walker AH, Weber BL, Rebbeck TR (1999) RESPONSE: re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 91:1588–1590

    PubMed  Google Scholar 

  • Ando Y, Tateishi T, Sekido Y, Yamamoto T, Satoh T, Hasegawa Y, Kobayashi S, Katsumata Y, Shimokata K, Saito H (1999) Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 91:1587–1590

    CAS  PubMed  Google Scholar 

  • Anttila S, Hukkanen J, Hakkola J, Stjernvall T, Beaune P, Edwards RJ, Boobis AR, Pelkonen O, Raunio H (1997) Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol 16:242–249

    PubMed  Google Scholar 

  • Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV et al (1989) Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 264:10388–10395

    CAS  Google Scholar 

  • Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, Weinryb I, Guida M, Hopkins PJ, Warner N, Hall J (1999) Population distribution and effects on drug metabolism of a genetic variant in the 5’ promoter region of CYP3A4. Clin Pharmacol Ther 66:288–294

    CAS  PubMed  Google Scholar 

  • Barwick JL, Quattrochi LC, Mills AS, Potenza C, Tukey RH, Guzelian PS (1996) Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. Mol Pharmacol 50:10–16

    CAS  PubMed  Google Scholar 

  • Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 95:12208–12213

    Article  CAS  PubMed  Google Scholar 

  • Bertilsson G, Berkenstam A, Blomquist P (2001) Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. Biochem Biophys Res Commun 280:139–144

    Article  CAS  PubMed  Google Scholar 

  • Blanco JG, Edick MJ, Hancock ML, Winick NJ, Dervieux T, Amylon MD, Bash RO, Behm FG, Camitta BM, Pui CH, Raimondi SC, Relling MV (2002) Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies. Pharmacogenetics 12:605–611

    Article  CAS  PubMed  Google Scholar 

  • Blumberg B, Sabbagh Jr W, Juguilon H, Bolado Jr J, van Meter CM, Ong ES, Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205

    CAS  PubMed  Google Scholar 

  • Boobis AR, Edwards RJ, Adams DA, Davies DS (1996) Dissecting the function of cytochrome P450. Br J Clin Pharmacol 42:81–89

    CAS  PubMed  Google Scholar 

  • Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, Klein K, Fromm MF, Nuessler AK, Neuhaus P, Zanger UM, Eichelbaum M, Wojnowski L (2002) Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277:24280–24288

    Article  CAS  PubMed  Google Scholar 

  • Castaneda-Hernandez G, Hoyo-Vadillo C, Palma-Aguirre JA, Flores-Murrieta FJ (1993) Pharmacokinetics of oral nifedipine in different populations. J Clin Pharmacol 33:140–145

    CAS  PubMed  Google Scholar 

  • Chang TK, Yu L, Maurel P, Waxman DJ (1997) Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 57:1946–1954

    CAS  PubMed  Google Scholar 

  • Chang TK, Bandiera SM, Chen J (2003) Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels. Drug Metab Dispos 31:7–10

    Article  CAS  PubMed  Google Scholar 

  • Chou FC, Tzeng SJ, Huang JD (2001) Genetic polymorphism of cytochrome P450 3A5 in Chinese. Drug Metab Dispos 29:1205–1209

    CAS  PubMed  Google Scholar 

  • Curi-Pedrosa R, Daujat M, Pichard L, Ourlin JC, Clair P, Gervot L, Lesca P, Domergue J, Joyeux H, Fourtanier G et al (1994) Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture. J Pharmacol Exp Ther 269:384–392

    CAS  PubMed  Google Scholar 

  • Cvetkovic R, Goa K (2003) Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 63:769–802

    CAS  PubMed  Google Scholar 

  • Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, Goldstein JA (2001) Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 299:825–831

    CAS  PubMed  Google Scholar 

  • Desai PB, Nallani SC, Sane RS, Moore LB, Goodwin BJ, Buckley DJ, Buckley AR (2002) Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen. Drug Metab Dispos 30:608–612

    Article  CAS  PubMed  Google Scholar 

  • Domanski TL, He YA, Harlow GR, Halpert JR (2000) Dual role of human cytochrome P450 3A4 residue Phe-304 in substrate specificity and cooperativity. J Pharmacol Exp Ther 293:585–591

    CAS  PubMed  Google Scholar 

  • Domanski TL, Finta C, Halpert JR, Zaphiropoulos PG (2001) cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 59:386–392

    CAS  PubMed  Google Scholar 

  • Drocourt L, Pascussi JM, Assenat E, Fabre JM, Maurel P, Vilarem MJ (2001) Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepatocytes. Drug Metab Dispos 29:1325–1331

    CAS  PubMed  Google Scholar 

  • Dussault I, Lin M, Hollister K, Wang EH, Synold TW, Forman BM (2001) Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J Biol Chem 276:33309–33312

    Article  CAS  PubMed  Google Scholar 

  • Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, Forman BM (2003) Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci USA 100:833–838

    Article  CAS  PubMed  Google Scholar 

  • Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedel E, Hustert E, Zanger UM, Brockmoller J, Klenk HP, Meyer UA, Khan KK, He YA, Halpert JR, Wojnowski L (2001) Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447–458

    CAS  PubMed  Google Scholar 

  • Evans AM (2000) Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 22:131–136

    CAS  PubMed  Google Scholar 

  • Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491

    Article  CAS  PubMed  Google Scholar 

  • Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NK, Lovett BD, Nowell PC, Blair IA, Rebbeck TR (1998) Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci USA 95:13176–13181

    Article  CAS  PubMed  Google Scholar 

  • Finta C, Zaphiropoulos PG (2000) The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 260:13–23

    Article  CAS  PubMed  Google Scholar 

  • Finta C, Zaphiropoulos PG (2002) Intergenic mRNA molecules resulting from trans-splicing. J Biol Chem 277:5882–5890

    CAS  PubMed  Google Scholar 

  • Fukuen S, Fukuda T, Matsuda H, Sumida A, Yamamoto I, Inaba T, Azuma J (2002a) Identification of the novel splicing variants for the hPXR in human livers. Biochem Biophys Res Commun 298:433–438

    Article  CAS  PubMed  Google Scholar 

  • Fukuen S, Fukuda T, Maune H, Ikenaga Y, Yamamoto I, Inaba T, Azuma J (2002b) Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population. Pharmacogenetics 12:331–334

    Google Scholar 

  • Garcia-Martin E, Martinez C, Pizarro RM, Garcia-Gamito FJ, Gullsten H, Raunio H, Agundez JA (2002) CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin Pharmacol Ther 71:196–204

    CAS  PubMed  Google Scholar 

  • Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587

    Article  CAS  PubMed  Google Scholar 

  • Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe HG, Brinkmann U, Klenk HP, Kleine K, Meyer UA, Wojnowski L (2001) Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11:111–121

    CAS  PubMed  Google Scholar 

  • Gibson GG, Plant NJ, Swales KE, Ayrton A, El-Sankary W (2002) Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Xenobiotica 32:165–206

    Article  CAS  PubMed  Google Scholar 

  • Gillam EM, Guo Z, Ueng YF, Yamazaki H, Cock I, Reilly PE, Hooper WD, Guengerich FP (1995) Expression of cytochrome P450 3A5 in Escherichia coli: effects of 5’ modification, purification, spectral characterization, reconstitution conditions, and catalytic activities [published erratum appears in Arch Biochem Biophys 1995 318:498]. Arch Biochem Biophys 317:374–384

    Article  CAS  Google Scholar 

  • Gillum JG, Israel DS, Polk RE (1993) Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 25:450–482

    CAS  PubMed  Google Scholar 

  • Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Schuetz E, Lim R, Lim HL, Ong AB, Lee HS (2002) Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol 20:3683–3690

    Article  CAS  PubMed  Google Scholar 

  • Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339

    CAS  PubMed  Google Scholar 

  • Goodwin B, Hodgson E, D’Costa DJ, Robertson GR, Liddle C (2002) Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 62:359–365

    Article  CAS  PubMed  Google Scholar 

  • Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, Repa JJ (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci USA 100:223–228

    Article  CAS  PubMed  Google Scholar 

  • Gorski JC, Hall SD, Jones DR, VandenBranden M, Wrighton SA (1994) Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 47:1643–1653

    CAS  PubMed  Google Scholar 

  • Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K, Inui K (2002) C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 12:451–457

    Article  CAS  PubMed  Google Scholar 

  • Grange JM, Winstanley PA, Davies PD (1994) Clinically significant drug interactions with antituberculosis agents. Drug Saf 11:242–251

    CAS  PubMed  Google Scholar 

  • Guengerich FP (1997) Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol 43:7–35

    CAS  PubMed  Google Scholar 

  • Haehner BD, Gorski JC, Vandenbranden M, Wrighton SA, Janardan SK, Watkins PB, Hall SD (1996) Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol 50:52–59

    PubMed  Google Scholar 

  • Hakkola J, Pasanen M, Purkunen R, Saarikoski S, Pelkonen O, Maenpaa J, Rane A, Raunio H (1994) Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochem Pharmacol 48:59–64

    CAS  PubMed  Google Scholar 

  • Hamzeiy H, Vahdati-Mashhadian N, Edwards HJ, Goldfarb PS (2002) Mutation analysis of the human CYP3A4 gene 5’ regulatory region: population screening using non-radioactive SSCP. Mutat Res 500:103–110

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T (1993) Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 218:585–595

    CAS  PubMed  Google Scholar 

  • Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403

    CAS  PubMed  Google Scholar 

  • Hirota N, Ito K, Iwatsubo T, Green CE, Tyson CA, Shimada N, Suzuki H, Sugiyama Y (2001) In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos 22:53–71

    Article  CAS  PubMed  Google Scholar 

  • Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478

    CAS  PubMed  Google Scholar 

  • Honkakoski P, Zelko I, Sueyoshi T, Negishi M (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18:5652–5658

    CAS  PubMed  Google Scholar 

  • Hoyo-Vadillo C, Castaneda-Hernandez G, Herrera JE, Vidal-Garate J, Moreno-Ramos A, Chavez F, Hong E (1989) Pharmacokinetics of nifedipine slow release tablet in Mexican subjects: further evidence for an oxidation polymorphism. J Clin Pharmacol 29:816–820

    CAS  PubMed  Google Scholar 

  • Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD (2001) Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 29:268–273

    CAS  PubMed  Google Scholar 

  • Huang Z, Fasco MJ, Figge HL, Keyomarsi K, Kaminsky LS (1996) Expression of cytochromes P450 in human breast tissue and tumors. Drug Metab Dispos 24:899–905

    Google Scholar 

  • Hukkanen J, Hakkola J, Anttila S, Piipari R, Karjalainen A, Pelkonen O, Raunio H (1997) Detection of mRNA encoding xenobiotic-metabolizing cytochrome P450s in human bronchoalveolar macrophages and peripheral blood lymphocytes. Mol Carcinog 20:224–230

    CAS  PubMed  Google Scholar 

  • Hukkanen J, Lassila A, Paivarinta K, Valanne S, Sarpo S, Hakkola J, Pelkonen O, Raunio H (2000) Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 22:360–366

    CAS  PubMed  Google Scholar 

  • Hukkanen J, Vaisanen T, Lassila A, Piipari R, Anttila S, Pelkonen O, Raunio H, Hakkola J (2003) Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther 304:745–752

    Article  CAS  PubMed  Google Scholar 

  • Hunt CM, Watkins PB, Saenger P, Stave GM, Barlascini N, Watlington CO, Wright Jr JT, Guzelian PS (1992) Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 51:18–23

    Google Scholar 

  • Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O (2001a) Natural protein variants of pregnane x receptor with altered transactivation activity toward cyp3a4. Drug Metab Dispos 29:1454–1459

    CAS  PubMed  Google Scholar 

  • Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Nuessler AC, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmoller J, Halpert JR, Zanger UM, Wojnowski L (2001b) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773–779

    CAS  PubMed  Google Scholar 

  • Janardan SK, Lown KS, Schmiedlin-Ren P, Thummel KE, Watkins PB (1996) Selective expression of CYP3A5 and not CYP3A4 in human blood. Pharmacogenetics 6:379–385

    CAS  PubMed  Google Scholar 

  • Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, Kliewer SA, Moore JT (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14:27–39

    CAS  PubMed  Google Scholar 

  • Jounaidi Y, Guzelian PS, Maurel P, Vilarem MJ (1994) Sequence of the 5’-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7. Biochem Biophys Res Commun 205:1741–1747

    Article  CAS  PubMed  Google Scholar 

  • Jounaidi Y, Hyrailles V, Gervot L, Maurel P (1996) Detection of CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein? Biochem Biophys Res Commun 221:466–470

    CAS  PubMed  Google Scholar 

  • Jover R, Bort R, Gomez-Lechon MJ, Castell JV (2001) Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting. Hepatology 33:668–675

    Article  CAS  PubMed  Google Scholar 

  • Kinirons MT, O’Shea D, Downing TE, Fitzwilliam AT, Joellenbeck L, Groopman JD, Wilkinson GR, Wood AJ (1993) Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men. Clin Pharmacol Ther 54:621–629

    CAS  PubMed  Google Scholar 

  • Kinirons MT, O’Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ, Wilkinson GR (1999) Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 66:224–231

    Google Scholar 

  • Kivisto KT, Fritz P, Linder A, Friedel G, Beaune P, Kroemer HK (1995) Immunohistochemical localization of cytochrome P450 3A in human pulmonary carcinomas and normal bronchial tissue. Histochem Cell Biol 103:25–29

    PubMed  Google Scholar 

  • Kivisto KT, Bookjans G, Fromm MF, Griese EU, Munzel P, Kroemer HK (1996a) Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. Br J Clin Pharmacol 42:387–389

    Google Scholar 

  • Kivisto KT, Griese EU, Fritz P, Linder A, Hakkola J, Raunio H, Beaune P, Kroemer HK (1996b) Expression of cytochrome P 450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours. Naunyn-Schmiedebergs Arch Pharmacol 353:207–212

  • Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82

    CAS  PubMed  Google Scholar 

  • Kocarek TA, Schuetz EG, Strom SC, Fisher RA, Guzelian PS (1995) Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes. Drug Metab Dispos 23:415–421

    CAS  PubMed  Google Scholar 

  • Koch I, Weil R, Wolbold R, Brockmoller J, Hustert E, Burk O, Nuessler A, Neuhaus P, Eichelbaum M, Zanger U, Wojnowski L (2002) Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 30:1108–1114

    Article  CAS  PubMed  Google Scholar 

  • Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB (1992) Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1871–1878

    CAS  PubMed  Google Scholar 

  • Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C, Wrighton SA, Merion RM, Watkins PB (1994) CYP3A gene expression in human gut epithelium. Pharmacogenetics 4:247–259

    CAS  PubMed  Google Scholar 

  • Kostrubsky VE, Lewis LD, Strom SC, Wood SG, Schuetz EG, Schuetz JD, Sinclair PR, Wrighton SA, Sinclair JF (1998) Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes. Arch Biochem Biophys 355:131–136

    Article  CAS  PubMed  Google Scholar 

  • Krivoruk Y, Kinirons MT, Wood AJ, Wood M (1994) Metabolism of cytochrome P4503A substrates in vivo administered by the same route: lack of correlation between alfentanil clearance and erythromycin breath test. Clin Pharmacol Ther 56:608–614

    CAS  PubMed  Google Scholar 

  • Krovat BC, Tracy JH, Omiecinski CJ (2000) Fingerprinting of cytochrome P450 and microsomal epoxide hydrolase gene expression in human blood cells. Toxicol Sci 55:352–360

    CAS  PubMed  Google Scholar 

  • Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391

    CAS  PubMed  Google Scholar 

  • Lakehal F, Wendum D, Barbu V, Becquemont L, Poupon R, Balladur P, Hannoun L, Ballet F, Beaune PH, Housset C (1999) Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium. Hepatology 30:1498–506

    CAS  PubMed  Google Scholar 

  • Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002a) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294

    Article  CAS  PubMed  Google Scholar 

  • Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S, Zhang J, Schuetz EG (2002b) Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 12:121–132

    Article  CAS  PubMed  Google Scholar 

  • Landes N, Pfluger P, Kluth D, Birringer M, Ruhl R, Bol GF, Glatt H, Brigelius-Flohe R (2003) Vitamin E activates gene expression via the pregnane X receptor. Biochem Pharmacol 65:269–273

    Article  CAS  PubMed  Google Scholar 

  • Lechevrel M, Casson AG, Wolf CR, Hardie LJ, Flinterman MB, Montesano R, Wild CP (1999) Characterization of cytochrome P450 expression in human oesophageal mucosa. Carcinogenesis 20:243–248

    CAS  PubMed  Google Scholar 

  • Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023

    CAS  PubMed  Google Scholar 

  • Li AP, Kaminski DL, Rasmussen A (1995) Substrates of human hepatic cytochrome P450 3A4. Toxicology 104:1–8

    Article  CAS  PubMed  Google Scholar 

  • Li J, Ning G, Duncan SA (2000) Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 14:464–474

    CAS  PubMed  Google Scholar 

  • Liddle C, Goodwin BJ, George J, Tapner M, Farrell GC (1998) Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes. J Clin Endocrinol Metab 83:2411–2416

    CAS  PubMed  Google Scholar 

  • Lin YS, Lockwood GF, Graham MA, Brian WR, Loi CM, Dobrinska MR, Shen DD, Watkins PB, Wilkinson GR, Kharasch ED, Thummel KE (2001) In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics 11:781–791

    Article  CAS  PubMed  Google Scholar 

  • Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62:162–172

    Article  CAS  PubMed  Google Scholar 

  • Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, Watkins PB (1994) Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test [published erratum appears in Drug Metab Dispos 1995 Mar;23(3):following table of contents]. Drug Metab Dispos 22:947–955

    CAS  PubMed  Google Scholar 

  • Lucey MR, Kolars JC, Merion RM, Campbell DA, Aldrich M, Watkins PB (1990) Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA. Lancet 335:11–15

    CAS  PubMed  Google Scholar 

  • Macphee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, Goldberg L, Holt DW (2002) Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 74:1486–1489

    CAS  PubMed  Google Scholar 

  • Marill J, Cresteil T, Lanotte M, Chabot GG (2000) Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol 58:1341–1348

    CAS  PubMed  Google Scholar 

  • Martin JE, Daoud AJ, Schroeder TJ, First MR (1999) The clinical and economic potential of cyclosporin drug interactions. Pharmacoeconomics 15:317–337

    CAS  PubMed  Google Scholar 

  • Masubuchi N, Li AP, Okazaki O (1998) An evaluation of the cytochrome P450 induction potential of pantoprazole in primary human hepatocytes. Chem Biol Interact 114:1–13

    Article  CAS  PubMed  Google Scholar 

  • McCune JS, Hawke RL, LeCluyse EL, Gillenwater HH, Hamilton G, Ritchie J, Lindley C (2000) In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone. Clin Pharmacol Ther 68:356–366

    Google Scholar 

  • McKinnon RA, Burgess WM, Hall PM, Roberts-Thomson SJ, Gonzalez FJ, McManus ME (1995) Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut 36:259–267

    CAS  PubMed  Google Scholar 

  • Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS (1986) Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci USA 83:5311–5315

    CAS  PubMed  Google Scholar 

  • Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000a) St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500–7502

    CAS  PubMed  Google Scholar 

  • Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA (2000b) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands [in process citation]. J Biol Chem 275:15122–15127

    Article  CAS  PubMed  Google Scholar 

  • Murray GI, Barnes TS, Sewell HF, Ewen SW, Melvin WT, Burke MD (1988) The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 25:465–475

    CAS  PubMed  Google Scholar 

  • Murray GI, Pritchard S, Melvin WT, Burke MD (1995) Cytochrome P450 CYP3A5 in the human anterior pituitary gland. FEBS Lett 364:79–82

    Article  CAS  PubMed  Google Scholar 

  • Murray GI, McFadyen MC, Mitchell RT, Cheung YL, Kerr AC, Melvin WT (1999) Cytochrome P450 CYP3A in human renal cell cancer. Br J Cancer 79:1836–1842

    Article  CAS  PubMed  Google Scholar 

  • Nakamoto T, Hase I, Imaoka S, Hiroi T, Oda Y, Asada A, Funae Y (2000) Quantitative RT-PCR for CYP3A4 mRNA in human peripheral lymphocytes: induction of CYP3A4 in lymphocytes and in liver by rifampicin. Pharmacogenetics 10:571–575

    Article  CAS  PubMed  Google Scholar 

  • Nowakowski-Gashaw I, Mrozikiewicz PM, Roots I, Brockmoller J (2002) Rapid quantification of CYP3A4 expression in human leukocytes by real-time reverse transcription-PCR. Clin Chem 48:366–370

    CAS  PubMed  Google Scholar 

  • Ohmori S, Fujiki N, Nakasa H, Nakamura H, Ishii I, Itahashi K, Kitada M (1998a) Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus. Res Commun Mol Pathol Pharmacol 100:15–28

    CAS  PubMed  Google Scholar 

  • Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M (1998b) Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells. Biochim Biophys Acta 1380:297–304

    Article  CAS  PubMed  Google Scholar 

  • Ourlin JC, Jounaidi Y, Maurel P, Vilarem MJ (1997) Role of the liver-enriched transcription factors C/EBP alpha and DBP in the expression of human CYP3A4 and CYP3A7. J Hepatol 2:54–62

    Article  Google Scholar 

  • Ozdemir V, Kalowa W, Tang BK, Paterson AD, Walker SE, Endrenyi L, Kashuba AD (2000) Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10:373–388

    CAS  PubMed  Google Scholar 

  • Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL, Perkins JD, Thummel KE (1997) Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 283:1552–1562

    CAS  PubMed  Google Scholar 

  • Paris PL, Kupelian PA, Hall JM, Williams TL, Levin H, Klein EA, Casey G, Witte JS (1999) Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer Epidemiol Biomarkers Prev 8:901–905

    CAS  PubMed  Google Scholar 

  • Pascussi JM, Drocourt L, Fabre JM, Maurel P, Vilarem MJ (2000a) Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol Pharmacol 58:361–372

    CAS  PubMed  Google Scholar 

  • Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ (2000b) Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol Pharmacol 58:1441–1450

    CAS  PubMed  Google Scholar 

  • Pascussi JM, Drocourt L, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ (2001) Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. Eur J Biochem 268:6346–6358

    Article  CAS  PubMed  Google Scholar 

  • Paulussen A, Lavrijsen K, Bohets H, Hendrickx J, Verhasselt P, Luyten W, Konings F, Armstrong M (2000) Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans [in process citation]. Pharmacogenetics 10:415–424

    CAS  PubMed  Google Scholar 

  • Pichard L, Fabre I, Fabre G, Domergue J, Saint Aubert B, Mourad G, Maurel P (1990) Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 18:595–606

    CAS  PubMed  Google Scholar 

  • Piipari R, Savela K, Nurminen T, Hukkanen J, Raunio H, Hakkola J, Mantyla T, Beaune P, Edwards RJ, Boobis AR, Anttila S (2000) Expression of CYP1A1, CYP1B1 and CYP3A, and polycyclic aromatic hydrocarbon-DNA adduct formation in bronchoalveolar macrophages of smokers and non-smokers. Int J Cancer 86:610–616

    Article  CAS  PubMed  Google Scholar 

  • Ratanasavanh D, Beaune P, Morel F, Flinois JP, Guengerich FP, Guillouzo A (1991) Intralobular distribution and quantitation of cytochrome P-450 enzymes in human liver as a function of age. Hepatology 13:1142–1151

    CAS  PubMed  Google Scholar 

  • Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB (1998) Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [published erratum appears in J Natl Cancer Inst 1999 91:1082]. J Natl Cancer Inst 90:1225–1229

    CAS  PubMed  Google Scholar 

  • Rodriguez-Antona C, Bort R, Jover R, Tindberg N, Ingelman-Sundberg M, Gomez-Lechon MJ, Castell JV (2003) Transcriptional regulation of human CYP3A4 basal expression by CCAAT enhancer-binding protein alpha and hepatocyte nuclear factor-3gamma. Mol Pharmacol 63:1180–1189

    Article  CAS  PubMed  Google Scholar 

  • Romani A, Guerra E, Trerotola M, Alberti S (2003) Detection and analysis of spliced chimeric mRNAs in sequence databanks. Nucleic Acids Res 31:e17

    Article  PubMed  Google Scholar 

  • Sakaeda T, Nakamura T, Okumura K (2003) Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics 4:397–410

    CAS  PubMed  Google Scholar 

  • Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G (2000) Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 6:2012–2020

    CAS  PubMed  Google Scholar 

  • Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ (2000) CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 67:48–56

    CAS  PubMed  Google Scholar 

  • Schellens JH, Soons PA, Breimer DD (1988) Lack of bimodality in nifedipine plasma kinetics in a large population of healthy subjects. Biochem Pharmacol 37:2507–2510

    Article  CAS  PubMed  Google Scholar 

  • Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Lown KS, Watkins PB (1997) Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3. Mol Pharmacol 51:741–754

    CAS  PubMed  Google Scholar 

  • Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Watkins PB (2001) Induction of cyp3a4 by 1alpha,25-dihydroxyvitamin d(3) is human cell line-specific and is unlikely to involve pregnane x receptor. Drug Metab Dispos 29:1446–1453

    CAS  PubMed  Google Scholar 

  • Schuetz EG (2001) Induction of cytochromes P450. Curr Drug Metab 2:139–147

    CAS  PubMed  Google Scholar 

  • Schuetz EG, Guzelian PS (1984) Induction of cytochrome P-450 by glucocorticoids in rat liver. II. Evidence that glucocorticoids regulate induction of cytochrome P-450 by a nonclassical receptor mechanism. J Biol Chem 259:2007–2012

    CAS  PubMed  Google Scholar 

  • Schuetz JD, Beach DL, Guzelian PS (1994) Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 4:11–20

    CAS  PubMed  Google Scholar 

  • Schuetz JD, Schuetz EG, Thottassery JV, Guzelian PS, Strom S, Sun D (1996) Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells. Mol Pharmacol 49:63–72

    CAS  PubMed  Google Scholar 

  • Sempoux C, Starkel P, Stevens M, Van Den Berge V, Horsmans Y (1999) Cytochrome P450 3A proteins are expressed in B lymphocytes but not in T lymphocytes. Pharmacogenetics 9:263–265

    CAS  PubMed  Google Scholar 

  • Shih PS, Huang JD (2002) Pharmacokinetics of midazolam and 1’-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab Dispos 30:1491–1496

    Article  CAS  PubMed  Google Scholar 

  • Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423

    CAS  PubMed  Google Scholar 

  • Smirlis D, Muangmoonchai R, Edwards M, Phillips IR, Shephard EA (2001) Orphan receptor promiscuity in the induction of cytochromes p450 by xenobiotics. J Biol Chem 276:12822–12826

    Article  CAS  PubMed  Google Scholar 

  • Spurdle AB, Goodwin B, Hodgson E, Hopper JL, Chen X, Purdie DM, McCredie MR, Giles GG, Chenevix-Trench G, Liddle C (2002) The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 12:355–366

    Article  CAS  PubMed  Google Scholar 

  • Standop J, Schneider MB, Ulrich A, Chauhan S, Moniaux N, Buchler MW, Batra SK, Pour PM (2002) The pattern of xenobiotic-metabolizing enzymes in the human pancreas. J Toxicol Environ Health A 65:1379–1400

    Article  CAS  PubMed  Google Scholar 

  • Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98:3369–3374

    Article  CAS  PubMed  Google Scholar 

  • Stein CM, Kinirons MT, Pincus T, Wilkinson GR, Wood AJ (1996) Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with rheumatoid arthritis receiving cyclosporine. Clin Pharmacol Ther 59:47–51

    Google Scholar 

  • Sumida A, Kinoshita K, Fukuda T, Matsuda H, Yamamoto I, Inaba T, Azuma J (1999) Relationship between mRNA levels quantified by reverse transcription-competitive PCR and metabolic activity of CYP3A4 and CYP2E1 in human liver. Biochem Biophys Res Commun 262:499–503

    CAS  PubMed  Google Scholar 

  • Sy SK, Ciaccia A, Li W, Roberts EA, Okey A, Kalow W, Tang BK (2002) Modeling of human hepatic CYP3A4 enzyme kinetics, protein, and mRNA indicates deviation from log-normal distribution in CYP3A4 gene expression. Eur J Clin Pharmacol 58:357–365

    Article  CAS  PubMed  Google Scholar 

  • Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584–590

    Article  CAS  PubMed  Google Scholar 

  • Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y (2001) Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 145:513–517

    CAS  PubMed  Google Scholar 

  • Tateishi T, Watanabe M, Moriya H, Yamaguchi S, Sato T, Kobayashi S (1999) No ethnic difference between Caucasian and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem Pharmacol 57:935–939

    CAS  PubMed  Google Scholar 

  • Tayeb MT, Clark C, Sharp L, Haites NE, Rooney PH, Murray GI, Payne SN, McLeod HL (2002) CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia. Oncol Rep 9:653–655

    CAS  PubMed  Google Scholar 

  • Thompson PD, Jurutka PW, Whitfield GK, Myskowski SM, Eichhorst KR, Dominguez CE, Haussler CA, Haussler MR (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299:730–738

    Article  CAS  PubMed  Google Scholar 

  • Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430

    CAS  PubMed  Google Scholar 

  • Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y, Ishizuka H, Kharasch E, Schuetz J, Schuetz (2001) Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. Mol Pharmacol 60:1399–1406

    CAS  PubMed  Google Scholar 

  • Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB (2003) The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9:220–224

    Article  CAS  PubMed  Google Scholar 

  • Van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J (2002) CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 48:1668–1671

    PubMed  Google Scholar 

  • Von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW (2001) No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 47:1048–1052

    PubMed  Google Scholar 

  • Walker AH, Jaffe JM, Gunasegaram S, Cummings SA, Huang CS, Chern HD, Olopade OI, Weber BL, Rebbeck TR (1998) Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online. Hum Mutat 12:289

    CAS  Google Scholar 

  • Wall JD, Pritchard JK (2003) Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4:587–597

    Article  CAS  PubMed  Google Scholar 

  • Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ, Wilkinson GR (2000) CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5’-promoter region polymorphism. Clin Pharmacol Ther 68:82–91

    CAS  PubMed  Google Scholar 

  • Wang H, Dick R, Yin H, Licad-Coles E, Kroetz DL, Szklarz G, Harlow G, Halpert JR, Correia MA (1998) Structure-function relationships of human liver cytochromes P450 3A: aflatoxin B1 metabolism as a probe. Biochemistry 37:12536–12545

    Article  CAS  PubMed  Google Scholar 

  • Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS (1987) Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029–1036

    CAS  PubMed  Google Scholar 

  • Watkins PB, Murray SA, Winkelman LG, Heuman DM, Wrighton SA, Guzelian PS (1989) Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients. J Clin Invest 83:688–697

    CAS  PubMed  Google Scholar 

  • Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, Redinbo MR (2001) The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329–2333

    Article  CAS  PubMed  Google Scholar 

  • Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003) 2.1 A crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry 42:1430–1438

    Article  CAS  PubMed  Google Scholar 

  • Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M (1999) Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5’-upstream regulatory region. Biochem Biophys Res Commun 259:201–205

    CAS  PubMed  Google Scholar 

  • Westlind A, Malmebo S, Johansson I, Otter C, Andersson TB, Ingelman-Sundberg M, Oscarson M (2001) Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 281:1349–1355

    Article  CAS  PubMed  Google Scholar 

  • Westlind-Johnsson A, Malembo S, Johansson A, Otter C, Andersson TB, Johansson I, Erwards RJ, Boobis AR, Ingelman-Sundberg M (2003) Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos 31:1–8

    Article  PubMed  Google Scholar 

  • Wilkinson GR (1996) Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 24:475–490

    CAS  Google Scholar 

  • Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, Wrighton SA (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 30:883–891

    Article  CAS  PubMed  Google Scholar 

  • Wojnowski L, Hustert E, Klein K, Goldammer M, Haberl M, Kirchheiner J, Koch I, Klattig J, Zanger U, Brockmoller J (2002) Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 94:630–631

    Article  PubMed  Google Scholar 

  • Wright MC (1999) The cytochrome P450 3A4 inducer metyrapone is an activator of the human pregnane X receptor. Biochem Soc Trans 27:387–391

    CAS  PubMed  Google Scholar 

  • Wrighton SA, Brian WR, Sari MA, Iwasaki M, Guengerich FP, Raucy JL, Molowa DT, Vandenbranden M (1990) Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol 38:207–213

    CAS  PubMed  Google Scholar 

  • Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS, Evans RM (2000a) Humanized xenobiotic response in mice expressing nuclear receptor SXR.” Nature 406:435–439

  • Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans (2000b) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14:3014–3023

    Article  CAS  PubMed  Google Scholar 

  • Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, Evans RM (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98:3375–3380

    Article  CAS  PubMed  Google Scholar 

  • Yokose T, Doy M, Taniguchi T, Shimada T, Kakiki M, Horie T, Matsuzaki Y, Mukai K (1999) Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues. Virchows Arch 434:401–411

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson Jr JR, Schuetz EG, Boguski MS (2001) The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11:555–572

    Article  CAS  PubMed  Google Scholar 

  • Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ (2003) Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 3:477–483

    CAS  PubMed  Google Scholar 

  • Zhu B, Liu ZQ, Chen GL, Chen XP, Ou-Yang DS, Wang LS, Huang SL, Tan ZR, Zhou HH (2003) The distribution and gender difference of CYP3A activity in Chinese subjects. Br J Clin Pharmacol 55:264–269

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Anna Westlind-Johnsson and colleagues for providing us with their paper prior to publication.

Author information

Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Oliver Burk

  2. Department of Clinical Pharmacology, Robert-Koch-Strasse 40, 37075, Goettingen, Germany

    Leszek Wojnowski

Authors
  1. Oliver Burk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leszek Wojnowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leszek Wojnowski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burk, O., Wojnowski, L. Cytochrome P450 3A and their regulation. Naunyn-Schmiedeberg's Arch Pharmacol 369, 105–124 (2004). https://doi.org/10.1007/s00210-003-0815-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-003-0815-3

Keywords

Search

Navigation