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CYP3A4  -  cytochrome P450, family 3, subfamily A,...

Homo sapiens

Synonyms: 1,8-cineole 2-exo-monooxygenase, Albendazole monooxygenase, Albendazole sulfoxidase, CP33, CP34, ...
 
 
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Disease relevance of CYP3A4

 

Psychiatry related information on CYP3A4

 

High impact information on CYP3A4

 

Chemical compound and disease context of CYP3A4

 

Biological context of CYP3A4

  • Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, has remained unclear [19].
  • Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject [20].
  • The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions [19].
  • PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates [21].
  • Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1 [21].
 

Anatomical context of CYP3A4

 

Associations of CYP3A4 with chemical compounds

 

Physical interactions of CYP3A4

  • Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays [30].
  • In this paper, we present a mutant that disrupts a hepatocyte-nuclear-factor-3/CCAAT-enhancer binding protein alpha binding site in the CYP3A4 proximal promoter [31].
  • HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site [32].
  • Difference spectra experiments revealed an NADPH-dependent peak at approximately 455 nm [metabolite-inhibitor (MI) complex] following incubation of all three drugs with CYP3A4 [33].
  • Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein [34].
 

Enzymatic interactions of CYP3A4

  • Delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is metabolized primarily through desalkylation catalyzed by CYP3A4 and CYP2D6 and by pyridine hydroxylation catalyzed by CYP3A4 [35].
  • Studies with 10 cDNA-expressed enzymes revealed that CYP3A4 catalyzed the formation of Nor and 4F at rates >100 times those of non-CYP3A enzymes and >100- and 50-fold higher than CYP3A5 and CYP3A7, respectively [36].
  • Incubation of olopatadine with cDNA-expressed human p450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4 [37].
  • The present study indicates that human liver microsomal CYP3A4 preferentially catalyzes the two NADPH- dependent metabolic routes of trofosfamide, which emphasizes the necessity for awareness of potential interactions with any coadministered drugs that are CYP3A4 substrates [38].
  • In contrast, CYP2E1 appears to be the main enzyme involved in the low affinity components of CA N1- and N7-demethylation while CA 8-hydroxylation is catalysed predominantly by a CYP3A isoform(s) [39].
 

Regulatory relationships of CYP3A4

  • The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics [30].
  • Both the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) are capable of regulating CYP3A4 and CYP2B6 gene expression [40].
  • When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450) [41].
  • On the other hand, cisapride strongly inhibited CYP3A4 and markedly inhibited CYP2C9 [42].
  • NaPB significantly induced levels of CYP3A4 apoprotein to 255% of control and RIF significantly induced levels of CYP2C19 and CYP3A4 apoproteins to 265 and 330% of control, respectively [43].
  • Results from this study suggest that DBP and E4BP4 might consist of a reciprocating mechanism in which DBP activates the transcription of the CYP3A4 gene during the time of day when DBP is abundant, and E4BP4 suppresses the transcription at other times of day [44].
 

Other interactions of CYP3A4

 

Analytical, diagnostic and therapeutic context of CYP3A4

References

  1. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. Zhou, C., Assem, M., Tay, J.C., Watkins, P.B., Blumberg, B., Schuetz, E.G., Thummel, K.E. J. Clin. Invest. (2006) [Pubmed]
  2. CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer. Zeigler-Johnson, C., Friebel, T., Walker, A.H., Wang, Y., Spangler, E., Panossian, S., Patacsil, M., Aplenc, R., Wein, A.J., Malkowicz, S.B., Rebbeck, T.R. Cancer Res. (2004) [Pubmed]
  3. CYP3A4 inducible model for in vitro analysis of human drug metabolism using a bioartificial liver. Iwahori, T., Matsuura, T., Maehashi, H., Sugo, K., Saito, M., Hosokawa, M., Chiba, K., Masaki, T., Aizaki, H., Ohkawa, K., Suzuki, T. Hepatology (2003) [Pubmed]
  4. Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice. Stedman, C., Robertson, G., Coulter, S., Liddle, C. J. Biol. Chem. (2004) [Pubmed]
  5. O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Relling, M.V., Nemec, J., Schuetz, E.G., Schuetz, J.D., Gonzalez, F.J., Korzekwa, K.R. Mol. Pharmacol. (1994) [Pubmed]
  6. Autoantibodies against cytochromes P-4502E1 and P-4503A in alcoholics. Lytton, S.D., Helander, A., Zhang-Gouillon, Z.Q., Stokkeland, K., Bordone, R., Aricò, S., Albano, E., French, S.W., Ingelman-Sundberg, M. Mol. Pharmacol. (1999) [Pubmed]
  7. Methadone--metabolism, pharmacokinetics and interactions. Ferrari, A., Coccia, C.P., Bertolini, A., Sternieri, E. Pharmacol. Res. (2004) [Pubmed]
  8. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. Taniguchi, R., Kumai, T., Matsumoto, N., Watanabe, M., Kamio, K., Suzuki, S., Kobayashi, S. J. Pharmacol. Sci. (2005) [Pubmed]
  9. Substrate dependent inhibition profiles of fourteen drugs on CYP3A4 activity measured by a high throughput LCMS/MS method with four probe drugs, midazolam, testosterone, nifedipine and terfenadine. Racha, J.K., Zhao, Z.S., Olejnik, N., Warner, N., Chan, R., Moore, D., Satoh, H. Drug Metab. Pharmacokinet. (2003) [Pubmed]
  10. Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics. Liangpunsakul, S., Kolwankar, D., Pinto, A., Gorski, J.C., Hall, S.D., Chalasani, N. Hepatology (2005) [Pubmed]
  11. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., Watkins, P.B., Daly, A., Wrighton, S.A., Hall, S.D., Maurel, P., Relling, M., Brimer, C., Yasuda, K., Venkataramanan, R., Strom, S., Thummel, K., Boguski, M.S., Schuetz, E. Nat. Genet. (2001) [Pubmed]
  12. The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Tirona, R.G., Lee, W., Leake, B.F., Lan, L.B., Cline, C.B., Lamba, V., Parviz, F., Duncan, S.A., Inoue, Y., Gonzalez, F.J., Schuetz, E.G., Kim, R.B. Nat. Med. (2003) [Pubmed]
  13. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Synold, T.W., Dussault, I., Forman, B.M. Nat. Med. (2001) [Pubmed]
  14. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Xie, W., Barwick, J.L., Downes, M., Blumberg, B., Simon, C.M., Nelson, M.C., Neuschwander-Tetri, B.A., Brunt, E.M., Guzelian, P.S., Evans, R.M. Nature (2000) [Pubmed]
  15. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Mani, S., Huang, H., Sundarababu, S., Liu, W., Kalpana, G., Smith, A.B., Horwitz, S.B. Clin. Cancer Res. (2005) [Pubmed]
  16. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Williams, D., Feely, J. Clinical pharmacokinetics. (2002) [Pubmed]
  17. Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Boocock, D.J., Brown, K., Gibbs, A.H., Sanchez, E., Turteltaub, K.W., White, I.N. Carcinogenesis (2002) [Pubmed]
  18. Engineering human cytochrome P450 enzymes into catalytically self-sufficient chimeras using molecular Lego. Dodhia, V.R., Fantuzzi, A., Gilardi, G. J. Biol. Inorg. Chem. (2006) [Pubmed]
  19. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. Lehmann, J.M., McKee, D.D., Watson, M.A., Willson, T.M., Moore, J.T., Kliewer, S.A. J. Clin. Invest. (1998) [Pubmed]
  20. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. Lown, K.S., Bailey, D.G., Fontana, R.J., Janardan, S.K., Adair, C.H., Fortlage, L.A., Brown, M.B., Guo, W., Watkins, P.B. J. Clin. Invest. (1997) [Pubmed]
  21. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. Goh, B.C., Lee, S.C., Wang, L.Z., Fan, L., Guo, J.Y., Lamba, J., Schuetz, E., Lim, R., Lim, H.L., Ong, A.B., Lee, H.S. J. Clin. Oncol. (2002) [Pubmed]
  22. Role of human microsomal and human complementary DNA-expressed cytochromes P4501A2 and P4503A4 in the bioactivation of aflatoxin B1. Gallagher, E.P., Wienkers, L.C., Stapleton, P.L., Kunze, K.L., Eaton, D.L. Cancer Res. (1994) [Pubmed]
  23. Role of human cytochrome P450 3A4 in metabolism of medroxyprogesterone acetate. Kobayashi, K., Mimura, N., Fujii, H., Minami, H., Sasaki, Y., Shimada, N., Chiba, K. Clin. Cancer Res. (2000) [Pubmed]
  24. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. van Heeswijk, R.P., Veldkamp, A., Mulder, J.W., Meenhorst, P.L., Lange, J.M., Beijnen, J.H., Hoetelmans, R.M. Antivir. Ther. (Lond.) (2001) [Pubmed]
  25. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Chang, T.K., Yu, L., Maurel, P., Waxman, D.J. Cancer Res. (1997) [Pubmed]
  26. Effect of cell density and epidermal growth factor on the inducible expression of CYP3A and CYP1A genes in human hepatocytes in primary culture. Greuet, J., Pichard, L., Ourlin, J.C., Bonfils, C., Domergue, J., Le Treut, P., Maurel, P. Hepatology (1997) [Pubmed]
  27. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. Paine, M.J., McLaughlin, L.A., Flanagan, J.U., Kemp, C.A., Sutcliffe, M.J., Roberts, G.C., Wolf, C.R. J. Biol. Chem. (2003) [Pubmed]
  28. Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas. Rodríguez-Antona, C., Leskelä, S., Zajac, M., Cuadros, M., Alvés, J., Moneo, M.V., Martín, C., Cigudosa, J.C., Carnero, A., Robledo, M., Benitez, J., Martínez-Delgado, B. Blood (2007) [Pubmed]
  29. Ligand binding to cytochrome P450 3A4 in phospholipid bilayer nanodiscs: the effect of model membranes. Nath, A., Grinkova, Y.V., Sligar, S.G., Atkins, W.M. J. Biol. Chem. (2007) [Pubmed]
  30. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Zhang, J., Kuehl, P., Green, E.D., Touchman, J.W., Watkins, P.B., Daly, A., Hall, S.D., Maurel, P., Relling, M., Brimer, C., Yasuda, K., Wrighton, S.A., Hancock, M., Kim, R.B., Strom, S., Thummel, K., Russell, C.G., Hudson, J.R., Schuetz, E.G., Boguski, M.S. Pharmacogenetics (2001) [Pubmed]
  31. Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element. El-Sankary, W., Bombail, V., Gibson, G.G., Plant, N. Drug Metab. Dispos. (2002) [Pubmed]
  32. Transcriptional regulation of human CYP3A4 basal expression by CCAAT enhancer-binding protein alpha and hepatocyte nuclear factor-3 gamma. Rodríguez-Antona, C., Bort, R., Jover, R., Tindberg, N., Ingelman-Sundberg, M., Gómez-Lechón, M.J., Castell, J.V. Mol. Pharmacol. (2003) [Pubmed]
  33. Differences in the inhibition of cytochromes P450 3A4 and 3A5 by metabolite-inhibitor complex-forming drugs. McConn, D.J., Lin, Y.S., Allen, K., Kunze, K.L., Thummel, K.E. Drug Metab. Dispos. (2004) [Pubmed]
  34. Pharmacokinetic interactions with rifampicin : clinical relevance. Niemi, M., Backman, J.T., Fromm, M.F., Neuvonen, P.J., Kivistö, K.T. Clinical pharmacokinetics. (2003) [Pubmed]
  35. Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6. Voorman, R.L., Payne, N.A., Wienkers, L.C., Hauer, M.J., Sanders, P.E. Drug Metab. Dispos. (2001) [Pubmed]
  36. Cytochrome P450 Involvement in the biotransformation of cisapride and racemic norcisapride in vitro: differential activity of individual human CYP3A isoforms. Pearce, R.E., Gotschall, R.R., Kearns, G.L., Leeder, J.S. Drug Metab. Dispos. (2001) [Pubmed]
  37. Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities. Kajita, J., Inano, K., Fuse, E., Kuwabara, T., Kobayashi, H. Drug Metab. Dispos. (2002) [Pubmed]
  38. Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide. May-Manke, A., Kroemer, H., Hempel, G., Bohnenstengel, F., Hohenlöchter, B., Blaschke, G., Boos, J. Cancer Chemother. Pharmacol. (1999) [Pubmed]
  39. Caffeine metabolism by human hepatic cytochromes P450: contributions of 1A2, 2E1 and 3A isoforms. Tassaneeyakul, W., Birkett, D.J., McManus, M.E., Tassaneeyakul, W., Veronese, M.E., Andersson, T., Tukey, R.H., Miners, J.O. Biochem. Pharmacol. (1994) [Pubmed]
  40. Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers. Faucette, S.R., Zhang, T.C., Moore, R., Sueyoshi, T., Omiecinski, C.J., Lecluyse, E.L., Negishi, M., Wang, H. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  41. Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. Faucette, S.R., Hawke, R.L., Shord, S.S., Lecluyse, E.L., Lindley, C.M. Drug Metab. Dispos. (2001) [Pubmed]
  42. Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338. Furuta, S., Kamada, E., Omata, T., Sugimoto, T., Kawabata, Y., Yonezawa, K., Wu, X.C., Kurimoto, T. Eur. J. Pharmacol. (2004) [Pubmed]
  43. Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices. Edwards, R.J., Price, R.J., Watts, P.S., Renwick, A.B., Tredger, J.M., Boobis, A.R., Lake, B.G. Drug Metab. Dispos. (2003) [Pubmed]
  44. Molecular basis for rhythmic expression of CYP3A4 in serum-shocked HepG2 cells. Takiguchi, T., Tomita, M., Matsunaga, N., Nakagawa, H., Koyanagi, S., Ohdo, S. Pharmacogenet. Genomics (2007) [Pubmed]
  45. Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Fontana, R.J., Lown, K.S., Paine, M.F., Fortlage, L., Santella, R.M., Felton, J.S., Knize, M.G., Greenberg, A., Watkins, P.B. Gastroenterology (1999) [Pubmed]
  46. The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity. Fontana, R.J., Turgeon, D.K., Woolf, T.F., Knapp, M.J., Foster, N.L., Watkins, P.B. Hepatology (1996) [Pubmed]
  47. Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. Drocourt, L., Ourlin, J.C., Pascussi, J.M., Maurel, P., Vilarem, M.J. J. Biol. Chem. (2002) [Pubmed]
  48. Intergenic mRNA molecules resulting from trans-splicing. Finta, C., Zaphiropoulos, P.G. J. Biol. Chem. (2002) [Pubmed]
  49. Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5. Mouly, S.J., Matheny, C., Paine, M.F., Smith, G., Lamba, J., Lamba, V., Pusek, S.N., Schuetz, E.G., Stewart, P.W., Watkins, P.B. Clin. Pharmacol. Ther. (2005) [Pubmed]
  50. Inhibition of human intestinal wall metabolism by macrolide antibiotics: effect of clarithromycin on cytochrome P450 3A4/5 activity and expression. Pinto, A.G., Wang, Y.H., Chalasani, N., Skaar, T., Kolwankar, D., Gorski, J.C., Liangpunsakul, S., Hamman, M.A., Arefayene, M., Hall, S.D. Clin. Pharmacol. Ther. (2005) [Pubmed]
  51. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Schuetz, E.G., Beck, W.T., Schuetz, J.D. Mol. Pharmacol. (1996) [Pubmed]
 
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