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Pharmacogenomics of CYP3A: considerations for HIV treatment

    Sukhwinder S Lakhman

    Department of Pharmaceutical Sciences, DYC School of Pharmacy, 320 Porter Avenue, Buffalo, NY 14201 USA

    ,
    Qing Ma

    Pharmacotherapy Research Center, University of Buffalo, Department of Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, Buffalo, NY 14260-1200, USA.

    &
    Gene D Morse

    † Author for correspondence

    Pharmacotherapy Research Center, University of Buffalo, Department of Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, Buffalo, NY 14260-1200, USA.

    Published Online:https://doi.org/10.2217/pgs.09.53

    The understanding of the cytochrome P450 3A SNP in antiretroviral therapy is important, because it is highly inducible, extremely polymorphic and metabolizes many of the drugs that are key components of highly active antiretroviral therapy regimens. This enzyme is prolific and promiscuous towards drug and xenobiotic substrate selection and it is also unpredictable among individuals, having a 5- to 20-fold variability in its ability to contribute to drug clearance. The importance of human CYP3A pharmacogenetics is also gaining attention in other established areas of pharmacotherapy as it may contribute to the goal of predicting efficacy and/or toxicity, specifically with the discovery of null allele CYP3A4*20. This review summarizes the current understanding, implications of genetic variation in the CYP3A enzymes, the central role of CYP3A in linking human genetics, the pharmacokinetics and resulting pharmacodynamic responses to certain antiretroviral drugs, and their eventual place in applied clinical pharmacotherapy.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • van Heeswijk RP: Optimized antiretroviral therapy: the role of therapeutic drug monitoring and pharmacogenomics. Expert Rev. Anti Infect. Ther.1,75–81 (2003).
    • Acosta EP, Gerber JG: Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res. Hum. Retroviruses18,825–834 (2002).
    • Catanzaro L, Slish J, Dicenzo R, Morse G: Drug interactions with antiretrovirals. Curr. HIV/AIDS Rep.1,89–96 (2004).▪ Along with [4] provides the comprehensive insight into the drug interaction in antiretroviral therapy.
    • Boffito M, Acosta E, Burger D et al.: Therapeutic drug monitoring and drug–drug interactions involving antiretroviral drugs. Antivir Ther.10,469–477 (2005).▪ Along with [3] provides the comprehensive insight into the drug interaction in antiretroviral therapy.
    • Wertheimer BZ, Freedberg KA, Walensky RP, Yazdanapah Y, Losina E: Therapeutic drug monitoring in HIV treatment: a literature review. HIV Clin. Trials7,59–69 (2006).
    • Droste JA, Koopmans PP, Hekster YA, Burger DM: TDM: therapeutic drug measuring or therapeutic drug monitoring? Ther. Drug Monit.27,412–416 (2005).
    • Burger D, Hugen P, Reiss P et al.: Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS17,1157–1165 (2003).
    • Morse G, Catanzaro L, Acosta E: Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy. Lancet Infect. Dis.6,215–225 (2006).▪ Therapeutic drug monitoring may provide a mechanism for individualizing the clinical pharmacodynamics of protease inhibitors based on patient-specific viral susceptibility.
    • Bruce RD, Altice FL: Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS20,783–784 (2006).
    • 10  Bruce RD, Altice FL, Gourevitch MN, Friedland GH: Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J. Acquir. Immune Defic. Syndr.41,563–572 (2006).
    • 11  Surratt HL, Inciardi JA, Weaver JC, Falu VM: Emerging linkages between substance abuse and HIV infection in St. Croix, US Virgin Islands. AIDS Care17(Suppl. 1),S26–S35 (2005).
    • 12  Beyrer C: Epidemiology Update and Transmission Factors. XVI International AIDS Conference. (2006).
    • 13  Chawarski MC, Mazlan M, Schottenfeld RS: Heroin dependence and HIV infection in Malaysia. Drug Alcohol. Depend.82(Suppl. 1),S39–S42 (2006).
    • 14  Saylors K, Jim N, Plasencia AV, Smith D: Faces of HIV/AIDS and substance abuse in Native American communities. J. Psychoactive Drugs37,241–246 (2005).
    • 15  Kapadia F, Vlahov D, Donahoe RM, Friedland G: The role of substance abuse in HIV disease progression: reconciling differences from laboratory and epidemiologic investigations. Clin. Infect. Dis.41,1027–1034 (2005).
    • 16  Sullivan LE, Metzger DS, Fudala PJ, Fiellin DA: Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users. Addiction100,150–158 (2005).
    • 17  Francis H: Substance abuse and HIV infection. Top. HIV Med.11,20–24 (2003).
    • 18  Kerr T, Wodak A, Elliott R, Montaner JS, Wood E: Opioid substitution and HIV/AIDS treatment and prevention. Lancet364,1918–1919 (2004).
    • 19  Verachai V, Phutiprawan T, Sawanpanyalert P: HIV infection among substance abusers in Thanyarak Institute On Drug Abuse, Thailand, 1987–2002. J. Med. Assoc. Thai.88,76–79 (2005).
    • 20  Mccance-Katz EF: Treatment of opioid dependence and coinfection with HIV and hepatitis C virus in opioid-dependent patients: the importance of drug interactions between opioids and antiretroviral agents. Clin. Infect. Dis.41(Suppl. 1),S89–S95 (2005).
    • 21  Bruce R, Mccance-Katz E, Kharasch E, Moody D, Morse G: Pharmacokinetic interactions between buprenorphine and antiretroviral medications. Clin. Infect. Dis.43,S216–S223 (2006).
    • 22  Baker J, Best A, Pade P, Mccance-Katz E: Effect of buprenorphine and antiretroviral agents on the QT interval in opioid-dependent patients. Ann. Pharmacother.40,392–396 (2006).
    • 23  Flexner CW: Advances in HIV pharmacology: protein binding, pharmacogenomics, and therapeutic drug monitoring. Top. HIV Med.11,40–44 (2003).
    • 24  Burger DM, van Rossum AM, Hugen PW et al.: Pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. Antimicrob. Agents Chemother.45,701–705 (2001).
    • 25  Cholerton S, Daly A, Idle J: The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol. Sci.13,434–439 (1992).
    • 26  Xie H-G, Wood AJ, Kim RB, Stein CM, Wilkinson GR: Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics5,243–272 (2004).
    • 27  Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC: The human intestinal cytochrome P450 ‘pie’. Drug Metab. Dispos.34,880–886 (2006).
    • 28  Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug Deliv. Rev.54,1271–1294 (2002).▪▪ Possible importance of CYP3A5 variants in the regulation, drug metabolism, efficacy and safety.
    • 29  Spurr N, Gough A, Stevenson K, Wolf CR: The human cytochrome P450 CYP3 locus: assignment to chromosome 7q22-qter. Hum Genet.81,171–174 (1989).
    • 30  Haehner BD, Gorski JC, Vandenbranden M et al.: Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol. Pharmacol.50,52–59 (1996).
    • 31  Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP: 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 (1994).
    • 32  Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev.34,83–448 (2002).
    • 33  Thummel KE, Kunze KL, Shen DD: Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv. Drug Deliv. Rev.27,99–127 (1997).
    • 34  Guengerich F: Cytochrome P-450 3A4: regulation and role in drug metabolism. Ann. Rev. Pharmacol. Toxicol.39,1–17 (1999).▪▪ Elucidation of the determinants of CYP3A activity, because of the interindividual variability present in the activity and its involvement in the metabolism of a large number of drugs.
    • 35  Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J. Natl Cancer Inst.90,1225–1229 (1998).
    • 36  Kuehl P, Zhang J, Lin Y et al.: Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet.27,383–391 (2001).
    • 37  Gonzalez FJ, Schmid BJ, Umeno M et al.: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA7,79–86 (1988).
    • 38  Walker A, Jaffe J, Gunasegaram S, Cummings SA, Huang CS, Chern H: 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 (1998).
    • 39  Hsieh K-P, Lin Y-Y, Cheng C-L et al.: Novel mutations of CYP3A4 in Chinese. Drug Metab. Dispos.29,268–273 (2001).
    • 40  Ball SE, Scatina J, Kao J et al.: Population distribution and effects on drug metabolism of a genetic variant in the 5´ promoter region of CYP3A4. Clin. Pharmacol. Ther.66,288–294 (1999).
    • 41  García-Martín E, Maartnez C, Pizarro RM et al.: CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin. Pharmacol. Ther.71,196–204 (2002).
    • 42  Paris PL, Kupelian PA, Hall JM et al.: Association between a CYP3A4 genetic variant and clinical presentation in African–American prostate cancer patients. Cancer Epidemiol. Biomarkers Prev.8,901–905 (1999).
    • 43  Sata F, Sapone A, Elizondo G et al.: 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 (2000).
    • 44  Hamzeiy H, Vahdati-Mashhadian N, Edwards HJ, Goldfarb PS: Mutation analysis of the human CYP3A4 gene 5´ regulatory region: population screening using non-radioactive SSCP. Mutat. Res.500,103–110 (2002).
    • 45  Saeki M, Saito Y, Nakamura T et al.: Single nucleotide polymorphisms and haplotype frequencies of CYP3A5 in a Japanese population. Hum. Mutat.21,653–670 (2003).
    • 46  Fukushima-Uesaka H, Saito Y, Watanabe H et al.: Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum. Mutat.23,100–108 (2004).
    • 47  Nelson DR, Koymans L, Kamataki T et al.: P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics6,1–42 (1996).
    • 48  Inoue K, Inazawa J, Nakagawa Het al.: Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. Jpn. J. Hum. Genet.37,133–138 (1992).
    • 49  Shchepotina EG, Vavilin VA, Goreva OB, Lyakhovich VV: Some mutations of exon-7 in cytochrome P450 gene 3A4 and their effect on 6β-hydroxylation of cortisol. Bull. Exp. Biol. Med.141,701–703 (2006).
    • 50  Reyes-Hernández OD, Lares-Asseff I, Sosa-Macias M, Vega L, Albores A, Elizondo G: A comparative study of CYP3A4 polymorphisms in Mexican Amerindian and Mestizo populations. Pharmacol. Ther.81,97–103 (2008).
    • 51  van Schaik R, van der Heiden I, van den Anker J, Lindemans J: CYP3A5 variant allele frequencies in Dutch Caucasians. Clin. Chem.48,1668–1671 (2002).
    • 52  Eiselt R, Domanski Tl, Zibat A et al.: Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics11,447–458 (2001).
    • 53  Murayama N, Nakamura T, Saeki M et al.: CYP3A4 gene polymorphisms influence testosterone 6β-hydroxylation. Drug Metab. Pharmacokinet.17,150–156 (2002).
    • 54  Dai D, Tang J, Rose R et al.: Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J. Pharmacol. Exp. Ther.299,825–831 (2001).
    • 55  Lee S-J, Bell DA, Coulter SJ, Ghanayem B, Goldstein JA: Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype. J. Pharmacol. Exp. Ther.313,302–309 (2005).
    • 56  Westlind-Johnsson A, Hermann R, Huennemeyer A et al.: Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin. Pharmacol. Ther.79,339–349 (2006).
    • 57  Jounaidi Y, Guzelian PS, Maurel P, Vilarem MJ: Sequence of the 5´-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7. Biochem. Biophy. Res. Commun.205,1741–1747 (1994).
    • 58  Paulussen A, Lavrijsen K, Bohets H et al.: Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans. Pharmacogenetics10,415–424 (2000).
    • 59  Lee S-J, Usmani K, Chanas B et al.: Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics13,461–472 (2003).
    • 60  Jounaïdi Y, Hyrailles V, Gervot L, Maurel P: Detection of a CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein? Biochem. Biophy. Res. Commun.221,466–470 (1996).
    • 61  Hustert E, Haberl M, Burk O et al.: The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics11,773–779 (2001).
    • 62  van Schaik Rh, de Wildt SN, Brosens R, van Fessem M, van den Anker JN, Lindemans J: The CYP3A4*3 allele: is it really rare? Clin. Chem.47,1104–1106 (2001).
    • 63  Hesselink DA, van Schaik RH, van der Heiden IP et al.: Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther.74,245–254 (2003).
    • 64  Thervet E, Anglicheau D, King B et al.: Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation76,1233–1235 (2003).
    • 65  Kivistö KT, Niemi M, Schaeffeler E et al.: Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics14,523–525 (2004).
    • 66  Balram C, Zhou Q, Cheung Y, Lee E: CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations. Eur. J. Clin. Pharmacol.59,123–126 (2003).
    • 67  Hiratsuka M, Takekuma Y, Endo N et al.: Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur. J. Clin. Pharmacol.58,417–421 (2002).
    • 68  Roy J-N, Lajoie J, Zijenah LS et al.: CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab. Dispos.33,884–887 (2005).
    • 69  Chou F-C, Tzeng S-J, Huang J-D: Genetic polymorphism of cytochrome P450 3A5 in Chinese. Drug Metab. Dispos.29,1205–1209 (2001).
    • 70  Shih P-S, Huang J-D: Pharmacokinetics of midazolam and 1´-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab. Dispos.30,1491–1496 (2002).
    • 71  Wong M, Balleine Rl, Collins M, Liddle C, Clarke Cl, Gurney H: CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy. Clin. Pharmacol. Ther.75,529–538 (2004).
    • 72  Mirghani R, Sayi J, Aklillu E et al.: CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population. Pharmacogenet. Genomics16,637–645 (2006).
    • 73  Lee S-J, van der Heiden IP, Goldstein JA, van Schaik RHN: a new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system. Drug Metab. Dispos.35,67–71 (2007).
    • 74  Domanski T, Finta C, Halpert JR, Zaphiropoulos PG: cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol. Pharmacol.59,386–392 (2001).
    • 75  Daly A, Cholerton S, Gregory W, Idle J: Metabolic polymorphisms. Pharmacol. Ther.57,129–160 (1993).
    • 76  Cauffiez C, Lo-Guidice J, Chevalier D et al.: First report of a genetic polymorphism of the cytochrome P450 3A43 (CYP3A43) gene: identification of a loss-of-function variant. Hum. Mutat.23,101–108 (2004).
    • 77  Zeigler-Johnson C, Friebel T, Walker AH et al.: CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer. Cancer Res.64,8461–8467 (2004).
    • 78  Kliewer SA, Moore JT, Wade L et al.: An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell92,73–82 (1998).
    • 79  Blumberg B, Sabbagh Jr W, Juguilon H et al.: SXR, a novel steroid and xenobiotic sensing nuclear receptor. Genes Dev.12,3195–3205 (1998).
    • 80  Bertilsson G, Berkenstam A, Blomquist P: Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. Biochem. Biophys. Res. Commun.280,139–144 (2001).
    • 81  Lehmann J, Mckee D, Watson M, Willson T, Moore J, Kliewer S: 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 (1998).
    • 82  Burk O, Wojnowski L: Cytochrome P450 3A and their regulation. Naunyn Schmiedebergs Arch. Pharmacol.369,105–124 (2004).
    • 83  Burk O, Koch I, Raucy J et al.: The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J. Biol. Chem.279,38379–38385 (2004).
    • 84  Burk O, Tegude H, Koch I et al.: Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J. Biol. Chem.277,24280–24288 (2002).
    • 85  El-Sankary W, Gibson GG, Ayrton A, Plant N: Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. Drug Metab. Dispos.29,1499–1504 (2001).
    • 86  Luo G, Cunningham M, Kim S et al.: CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab. Dispos.30,795–804 (2002).
    • 87  Hebert M, Roberts J, Prueksaritanont T, Benet L: Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin. Pharmacol. Ther.52,453–457 (1992).
    • 88  Modry D, Stinson E, Oyer P: Acute rejection and massive cyclosporine requirements in heart transplantation. Transplantation.39,313–314 (1985).
    • 89  Lin J, Lu A: Inhibition and induction of cytochrome P450 and the clinical implications. Clin. Pharmacokinet.35,361–390 (1998).
    • 90  Beresford A: CYP1A1: friend or foe? Drug Metab. Rev.25,503–517 (1993).
    • 91  Piacenti FJ: An update and review of antiretrovirals therapy. Pharmacotherapy26,1111–1133 (2006).
    • 92  Thummel KE, Wilkinson GR: In vitro and in vivo drug interactions involving human CYP3A. Ann. Rev. Pharmacol. Toxicol.38,389–430 (1998).
    • 93  Mahgoub A, Dring LG, Idle JR, Lancaster R, Smith RL: Polymorphic hydroxylation of debrisoquine in man. Lancet310,584–586 (1977).
    • 94  Li AP, Rasmussen A, Xu L, Kaminski Dl: Rifampicin induction of lidocaine metabolism in cultured human hepatocytes. J. Pharmacol. Exp. Ther.274,673–677 (1995).
    • 95  Schuetz E, Schuetz J, Strom S et al.: Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology18,1254–1262 (1993).
    • 96  Gibbs JP, Hyland R, Youdim K: Minimizing polymorphic metabolism in drug discovery: evaluation of the utility of in vitro methods for predicting pharmacokinetic consequences associated with CYP2D6 metabolism. Drug Metab. Dispos.34,1516–1522 (2006).
    • 97  Saiki RK, Scharf S, Faloona F et al.: Enzymatic amplification of β-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science230,1350–1354 (1985).
    • 98  Rodríguez-Antona C, Jande M, Rane A, Ingelman-Sundberg M: Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal livers. Clin. Pharmacol. Ther.77,259–270 (2005).
    • 99  Lee S-J, Jusko J, Salaita CG et al.: Reduced methylprednisolone clearance causing prolonged pharmacodynamics in a healthy subject was not associated with CYP3A5*3 allele or a change in diet composition. J. Clin. Pharmacol.46,515–526 (2006).
    • 100  Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ, Wilkinson GR: CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B 5´-promoter region polymorphism. Clin. Pharmacol. Ther.68,82–91 (2000).
    • 101  Cheung C, Op Den Buijsch R, Wong K et al.: Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients. Pharmacogenomics7,563–574 (2006).
    • 102  Lee S-J, Goldstein J: Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics6,357–371 (2005).
    • 103  Intemann CD, Thye T, Sievertsen J, Owusu-Dabo E, Horstmann RD, Meyer CG: Genotyping of IRGM tetranucleotide promoter oligorepeats by fluorescence resonance energy transfer. BioTechniques46,58–60 (2009).
    • 104  Maurel P: The CYP3 family. In: Cytochromes P450: Metabolic and Toxicological Aspects. Edition. Ioannides C (Ed.). CRC, FL, USA, 241–270 (1996).
    • 105  Quattrochi LC, Guzelian PS: CYP3A regulation: from pharmacology to nuclear receptors. Drug Metab. Dispos.29,615–622 (2001).
    • 106  Rae JM, Johnson MD, Lippman ME, Flockhart DA: Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J. Pharmacol. Exp. Ther.299,849–857 (2001).
    • 107  Bell AW, Michalopoulos GK: Phenobarbital regulates nuclear expression of HNF-4α in mouse and rat hepatocytes independent of CAR and PXR. Hepatology44,186–194 (2006).
    • 108  Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol. Pharm. Bull.26,510–517 (2003).
    • 109  Hukkanen J, Lassila A, Paivarinta K et al.: 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 (2000).
    • 110  Zhou SF, Xue CC, Yu XQ, Li C, Wang G: Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther. Drug Monit.29,687–710 (2007).
    • 111  Cotreau M, von Moltke L, Greenblatt D: The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin. Pharmacokinet.44,33–60 (2005).
    • 112  Koudriakova T, Iatsimirskaia E, Utkin I et al.: Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: Mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab. Dispos.26,552–561 (1998).
    • 113  Chiba M, Hensleigh M, Lin JH: Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes: major role of CYP3A. Biochem. Pharmacol.53,1187–1195 (1997).
    • 114  Kumar GN, Rodrigues AD, Buko AM, Denissen JF: Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J. Pharmacol. Exp. Ther.277,423–431 (1996).
    • 115  Zalma A, von Moltke LI, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ: In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viral protease inhibitors. Biological Psychiatry47,655–661 (2000).
    • 116  Greenblatt DJ, von Moltke Ll, Harmatz JS et al.: Differential impairment of triazolam and zolpidem clearance by ritonavir. J. Acquir. Immune Defic. Syndr.24,129–136 (2000).
    • 117  von Moltke Ll, Durol AL, Duan SX, Greenblatt DJ: Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. Eur. J. Clin. Pharmacol.56,259–261 (2000).
    • 118  Eagling V, Back D, Barry M: Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br. J. Clin. Pharmacol.44,190–194 (1997).
    • 119  Chiba M, Hensleigh M, Nishime JA, Balani SK, Lin JH: Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab. Dispos.24,307–314 (1996).
    • 120  Barry M, Gibbons S, Back D, Mulcahy F: Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. Clin. Pharmacokinet.32,194–209 (1997).
    • 121  Kumar GN, Dykstra J, Roberts EM et al.: Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug–drug interaction. Drug Metab. Dispos.27,902–908 (1999).
    • 122  Goldsmith Dr, Perry CM: Atazanavir. Drugs63,1679–1693 (2003).
    • 123  Le Tiec C, Barrail A, Goujard C, Taburet A: Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin. Pharmacokinet.44,1035–1050 (2005).
    • 124  Lillibridge JH, Liang BH, Kerr BM et al.: Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab. Dispos.26,609–616 (1998).
    • 125  Zhang KE, Wu E, Patick AK et al.: Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities. Antimicrob. Agents Chemother.45,1086–1093 (2001).
    • 126  Westlind A, Malmebo S, Johansson I et al.: Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem. Biophys. Res. Commun.281,1349–1355 (2001).
    • 127  Kharasch Ed, Hoffer C, Whittington D, Sheffels P: Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin. Pharmacol. Ther.76,250–269 (2004).
    • 128  Goto M, Masuda S, Kiuchi T et al.: CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics14,471–478 (2004).
    • 129  Greenblatt DJ, von Moltke Ll, Harmatz JS et al.: Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. Clin. Pharmacol. Ther.74,121–129 (2003).
    • 130  Rotger M, Colombo S, Furrer H et al.: Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet. Genomics.15,1–5 (2005).
    • 131  Wang J, Sonnerborg A, Rane A et al.: Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet. Genomics.16,191–198 (2006).
    • 132  Stebbing J, Bower M: Comparative pharmacogenomics of antiretroviral and cytotoxic treatments. Lancet Oncol.7,61–68 (2006).
    • 133  Rodriguez-Novoa S, Barreiro P, Jimenez-Nacher I, Soriano V: Overview of the pharmacogenetics of HIV therapy. Pharmacogenomics J.6,234–245 (2006).
    • 134  Schwartz DH, Iyengar S: Toward genetic rationalization of antiretroviral therapy for HIV. AIDS19,975–977 (2005).
    • 135  Haas DW: Will pharmacogenomic discoveries improve HIV therapeutics? Top. HIV Med.13,90–95 (2005).
    • 136  Haas DW, Wilkinson GR, Kuritzkes DR et al.: A multi-investigator/institutional DNA bank for AIDS-related human genetic studies: AACTG Protocol A5128. HIV Clin. Trials4,287–300 (2003).
    • 137  Haas DW: Pharmacogenomics and HIV therapeutics. J. Infect. Dis.191,1397–1400 (2005).
    • 138  Haas DW, Ribaudo HJ, Kim RB et al.: Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS18,2391–2400 (2004).
    • 139  Haas DW, Smeaton LM, Shafer RW et al.: Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. J. Infect. Dis.192,1931–1942 (2005).
    • 140  Zhang X, Liu ZH, Zheng JM et al.: Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin. Transplant.19,638–643 (2005).
    • 141  Kukanich B, Lascelles BD, Aman AM, Mealey KL, Papich MG: The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs. J. Vet. Pharmacol. Ther.28,461–466 (2005).
    • 142  Christians U, Schmitz V, Haschke M: Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin. Drug Metab. Toxicol.1,641–654 (2005).
    • 143  Jones K, Hoggard P, Sales S, Khoo S, Davey R, Back D: Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport. AIDS15,675–681 (2001).
    • 144  Anglicheau D, Thervet E, Etienne I et al.: CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin. Pharmacol. Ther.75,422–433 (2004).
    • 145  Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG: Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J. Pharmacol. Exp. Ther.303,323–332 (2002).
    • 146  Fellay J, Marzolini C, Meaden ER et al.: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet359,30–36 (2002).
    • 147  Rodriguez Novoa S, Barreiro P, Rendon A et al.: Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C>T polymorphism at the multidrug resistance gene 1. Clin. Infect. Dis.42,291–295 (2006).
    • 148  Bertilsson G, Berkenstam A, Blomquist P: Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. Biochem. Biophy. Res. Commun.280,139–144 (2001).
    • 149  Penzak S, Kabuye G, Mugyenyi P et al.: Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med.8,86–91 (2007).
    • 150  Haas DW, Bartlett JA, Andersen JW et al.: Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. Clin. Infect. Dis.43783–786 (2006).
    • 151  Mouly SJ, Matheny C, Paine MF et al.: Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5. Clin. Pharmacol. Ther.78,605–618 (2005).
    • 152  Josephson F, Allqvist A, Janabi M et al.: CYP3A5 genotype has an impact on the metabolism of the HIV protease inhibitor saquinavir. Clin. Pharmacol. Ther.81,708–712 (2007).
    • 153  Anderson P, Lamba J, Aquilante Cl, Schuetz E, Fletcher CV: Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J. Acquir. Immune Defic. Syndr.42,441–449 (2006).
    • 154  Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS21,41–46 (2007).
    • 155  Lamba J, Strom S, Venkataramanan R et al.: MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin. Pharmacol. Ther.79,325–338 (2006).
    • 156  Ma Q, Brazeau D, Forrest A, Morse GD: Advances in pharmacogenomics of antiretrovirals: an update. Pharmacogenomics8,1169–1178 (2007).
    • 157  Hopkins MM, Ibarreta D, Gaisser S et al.: Putting pharmacogenetics into practice. Nat. Biotech.24,403–410 (2006).
    • 158  Staddon S, Arranz M, Mancama D, Mata I, Kerwin RW: Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl.)162,18–23 (2002).
    • 159  Aquilante CL, Langaee TY, Lopez LM et al.: Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin. Pharmacol. Ther.79,291–302 (2006).
    • 160  Martin AM, Nolan D, Gaudieri S et al.: Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. PNAS101,4180–4185 (2004).
    • 161  Abraham J, Earl H, Pharoah P, Caldas C: Pharmacogenetics of cancer chemotherapy. Biochim. Biophys. Acta1766,168–183 (2006).
    • 162  Weinshilboum R, Wang L: Pharmacogenomics: bench to bedside. Nat. Rev. Drug Discov.3,739–748 (2004).
    • 163  Roden DM, Altman RB, Benowitz NL et al.: Pharmacogenomics: challenges and opportunities. Ann. Intern. Med.145,749–757 (2006).
    • 164  Murray M: Induction and inhibition of CYPs and implications for medicine. Mol. Aspects Med.20,34–137 (1999).
    • 165  Winzer R, Langmann P, Zilly M et al.: No influence of the P-glycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naive HIV-positive patients. Ann. Clin. Microbiol. Antimicrob.4,3 (2005).
    • 166  Wilkinson GR: Genetic variability in cytochrome P450 3A5 and in vivo cytochrome P450 3A activity: some answers but still questions. Clin. Pharmacol. Ther.76,99–103 (2004).
    • 167  Quirk E, Mcleod H, Powderly W: The pharmacogenetics of antiretroviral therapy: a review of studies to date. Clin. Infect. Dis.39,98–106 (2004).
    • 168  Martin A, Nolan D, Gaudieri S, Phillips E, Mallal S: Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity. Pharmacogenomics5,643–655 (2004).
    • 169  Saitoh A, Singh K, Powell C et al.: An MDR1 -3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS19,371–380 (2005).
    • 170  Nolan D, Gaudieri S, Mallal S: Pharmacogenetics: a practical role in predicting antiretroviral drug toxicity? J. HIV Ther.8,36–41 (2003).
    • 171  Haas DW, Wu H, Li H et al.: MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study. J. Acquir. Immune Defic. Syndr.34,295–298 (2003).
    • 172  Motsinger A, Ritchie M, Shafer RW et al.: Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study. Pharmacogenet. Genomics.16,837–845 (2006).
    • 173  Rae JM, Johnson MD, Lippman ME, Flockhart DA: Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes:studies with cDNA and oligonucleotide arrays. J. Pharmacol. Exp. Ther.299,849–857 (2001).
    • 174  Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol. Pharm. Bull.26,510–517 (2003).
    • 175  Luo G, Cunningham M, Kim S et al.: CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab. Dispos.30,795–804 (2002).
    • 176  Hukkanen J, Lassila A, Paivarinta K et al.: 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 (2000).
    • 177  Krusekopf S, Roots I, Kleeberg U: Differential drug-induced mRNA expression of human CYP3A4 compared with CYP3A5, CYP3A7 and CYP3A43. Eur. J. Pharmacol.466,7–12 (2003).
    • 178  Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab. Dispos.31,533–539 (2003).