2About CYP2B6 Located on chromosome 19 Makes up about 2-10% of hepatic CYP contentAlso expressed in brain (significantly higher in smokers and alcoholics)Metabolizes 4% of the top 200 drugsHighly inducible (some substrates also autoinduce, and it is also inducible in stressed conditions, e.g. fasting)High interindividual variation
4Inhibitors and Inducers of 2B6 Clopidogrel- Potent inhibitorOC/HRTEfavirenzParoxetineFluoxetineChlorpyrifos (insecticide)FluvoxamineSertralineMemantineThiotepaNelfinavirTiclopidine- Potent inhibitorClotrimazole & ItraconazoleRaloxifeneInducersLopinavir/RitonavirPhenytoinPhenobarbitalRifampinDexamethasoneCarbamazepineMetamizoleEfavirenz (autoinduces)Cyclophosphamide (auto)Artemisinin (autoinduces)Endosulfan
5DefinitionsCYPs (or Cytochrome P450 genes) produce enzymes involved in synthesis and breakdown of molecules and are subdivided into groups and subfamilies (CYP3A4, CYP2C9, etc). Enzymes mostly found in liver, but also found throughout body (brain, intestine, etc). Different combinations of polymorphisms in these genes are haplotypes (CYP2B6*6, CYP2B6*1).Haplotype= a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted togetherNon-synonymous= a SNP in which both wildtype and mutant forms lead to the same polypeptide sequence is termed synonymous (sometimes called a silent mutation) — if a different polypeptide sequence is produced they are nonsynonymous.SNP nomenclature:
6Haplotypes with decreased activity in vivo CYP2B6*6, CYP2B6*16, CYP2B6*26Haplotype with increased activity in vivoCYP2B6*4
7Where haplotypes are important in regard to therapy: Efavirenz for HIV treatmentCyclophosphamide for chemotherapyBupropion for smoking cessationCardiac side effects and death from methadone
8Effect on Efavirenz Therapy CYB2B6*6 haplotype CYP2B6*6 has two nonsynonymous variants:CYP2B6:516G>T AND CYP2B6:785A>GWith or without additional promoter variants:-1456T>G AND -750T>C or T>CPresent in 15-40% Asian, >50% Black population, 26% CaucasianSuccessful Efavirenz dose reduction to 400mg or 200mg was done for CYP2B6*6/*6 and *6/*26 carriers whose EFV concentrations were extremely high (>6000 ng/ml).
9Effect on Efavirenz Therapy 516G>T The 516G>T SNP that is present in CYP2B6*6 is also present in *7, *9, and *13Presence is associated with 3-fold decrease in CYP2B6 activityThe TT genotype is associated with increased efavirenz exposure (resulting in CNS side effects). Also predicts increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens983T>CDefining SNP of CYP2B6*18 allele, and found in linkage in the CYP2B6*16 haplotypeNot observed in Asians, Caucasians. 4-9% Blacks, low frequency HispanicsAssociated with increased efavirenz and nevirapine exposure
10Effect on Bupropion Therapy CYP2B6*4 Presence of 785A>G SNPHigh frequency in ethnic groups(15% Asian, 50% Black)Clearance of bupropionincreased 1.66-fold*1/*4 genotype had AUC of hydroxybupropion (active metabolite formed by 2B6) increased by 25% compared to *1/*1
11Effect on Cyclophosphamide Therapy CYP2B6*6 homozygotes have significantly higher clearance and shorter half-life of cyclophosphamide compared to CYP2B6*1 heterozygotes and homozygotesSpecific SNPs in the promoter region or introns (-2320T>C, -750T>C, 15582C>T of intron 3, or 18492T>C) of CYP2B6 affected cyclophosphamide activation to 4-hydroxycyclophosphamide (AUC of 4-hydroxycyclophosphamide is significantly related to leukocytopenia and neutropenia). This knowledge can help predict adverse effects.
12Effect on Doxorubicin and Cyclophosphamide Therapy Higher dose delay (indicative of higher toxicity) was seen in CYP2B6*2 and CYP2B6*5CYP2B6*2, CYP2B6*8, CYP2B6*9, CYP2B6*4 were associated with a worse outcomeBray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6):
13Effect on Methadone Therapy Methadone is a racemic mixture(R)-methadone: narcotic effect by activating µ-opiod receptor(S)-methadone: inhibits cardiac potassium channelCYP2B6 is selective for (S)-methadone metabolismHaving decreased CYP2B6 activity increases plasma concentrations of (S)-methadone (but not (R)-methadone) and increase risk of cardiac side effects and death.*6/*6 genotype had increased risk of prolonged QTc
14ReferencesBray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6):Kirchheiner J, Klein C, Meineke I, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003;13:619–26.T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal 2001; 1:Thorn CF, Lamba JK, Lamba V, Klein, Teri E, Altman RB. PharmGKB summary: very important pharmacogene information for CYP2B6. Pharmacogenet Genomics 2010; 20(8):Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9:598–610.Wynn, Gary H, Jessica R Oesterheld, Kelly L Cozza, and Scott C Armstrong. Clinical Manual of Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Publishing, 2009.
15ReferencesEap CB, Crettol S, Rougier JS, Schlapfer J, Sintra Grilo L, Deglon JJ, Besson J, Croquette-Krokar M, Carrupt PA, Abriel H. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81(5):719–28.Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, Clifford DB, Marzolini C, Fletcher CV, Tashima KT, Kuritzkes DR, Acosta EP. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42(3):401–7.Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, Takata N, Kimura A, Koike T, Gejyo F, Matsushita S, Shirasaka T, Kimura S, Oka S. Clin Infect Dis. 2007;45(9):1230–7.Nakajima M, Komagata S, Fujiki Y, Kanada Y, Ebi H, Itoh K, Mukai H, Yokoi T, Minami H. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Pharmacogenet Genomics. 2007;17(6):431–45.