Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P4502B6 in human liver microsomes
Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P4502B6 in human liver microsomes
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DOI：
10.1097/00008571-200404000-00002
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发表时间：
2004-04-01
期刊：
影响因子：
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通讯作者：
Court, MH
中科院分区：
文献类型：
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作者：
Hesse, LM;He, P;Court, MH
安非他酮主要在人肝脏中通过细胞色素P450（CYP）2136代谢，细胞色素P450（CYP）2136是一种在表达和催化方面表现出高度个体间变异性的亚型。本研究的目的是通过对充分表征的人肝库（n = 54）进行综合表型-基因型分析，确定这种变异性的潜在机制。微粒体安非他酮羟基化活性（超过45倍）和CYP 2B 6蛋白含量（超过288倍）存在显著变异性，蛋白和活性值之间具有良好的相关性（r（s）= 0.88）。CYP 2B 6 mRNA水平显示与CYP 2B 6蛋白的变异性较小（11.3倍）和相关性较差（r（s）= 0.44），这是由于20-30%的肝脏含有大量CYP 2B 6 mRNA，但CYP 2B 6蛋白较低。对肝脏的常见编码多态性（Q172 H、K262 R和R487 C）和通过基因启动子测序至~ 3000 bp鉴定的14种额外变异进行基因分型。在推测的14种单倍型中，*1A（参考）、*1H（-2320t>c;-750t>c）和 * 6 B（-1456t>c;-750t>c; Q172 H; K262 R）最常见，频率分别为0.28、0.20和0.26。饮酒史（P = 0.011）和 * 6 B单倍型（P = 0.011）被确定为安非他酮羟基化的重要预测因子。考虑到这些变量对CYP 2B 6 mRNA和蛋白水平的影响，表明饮酒与CYP 2B 6基因转录增强相关，但至少一个 * 6 B等位基因的存在降低了转录后水平对安非他酮羟基化的影响。总之，本研究的结果表明，安非他酮羟基化的个体间变异性是环境和遗传因素对CYP 2B 6基因功能的相互作用的结果。药物遗传学14：225-238 0 2004 Lippincott威廉姆斯威尔金斯
Bupropion is primarily metabolized in human liver by cytochrome P450 (CYP) 2136, an isoform that shows high interindividual variability in expression and catalysis. The aim of this study was to identify mechanisms underlying this variability through comprehensive phenotype-genotype analysis of a well-characterized human liver bank (n = 54). There was substantial variability in microsomal bupropion hydroxylation activities (over 45-fold) and CYP2B6 protein content (over 288-fold), with excellent correlation between protein and activity values (r(s) = 0.88). CYP2B6 mRNA levels showed less variability (11 3-fold) and poorer correlation (r(s) = 0.44) to CYP2B6 protein resulting from 20-30% of livers that contained substantial CYP2B6 mRNA, but low CYP2B6 protein. Livers were genotyped for the common coding polymorphisms (Q172H, K262R and R487C) and 14 additional variations identified by sequencing of the gene promoter to -3000 bp. Of 14 haplotypes that were inferred, *1A (reference), *1H (- 2320t>c; - 750t>c) and *6B (- 1 456t>c; - 750t>c; Q172H; K262R) were most common with frequencies of 0.28,0.20 and 0.26, respectively. Alcohol use history (P = 0.011) and *6B haplotype (P = 0.011) were identified as significant predictors of bupropion hydroxylation. A consideration of the effects of these variables on CYP2B6 mRNA and protein levels suggests that alcohol use is associated with enhanced CYP2B6 gene transcription, but the presence of at least one *6B allele reduces this effect on bupropion hydroxylation at the post-transcriptional level. In conclusion, the results of this study indicate that interindividual variability in bupropion hydroxylation is a consequence of interactions between environmental and genetic influences on CYP2B6 gene function. Pharmacogenetics 14:225-238 0 2004 Lippincott Williams Wilkins