Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence.
Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence.
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CYP2D6 代谢基因缺陷可防止口服阿片类药物依赖。
DOI：
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
Edward M. Sellers1
中科院分区：
文献类型：
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作者：
R. Tyndale;K. Droll;Edward M. Sellers1
口服阿片类药物（如可待因、羟考酮和氢可酮）被细胞色素CYP2D6代谢为活性增加的代谢物（如吗啡、氧吗啡酮和氢吗啡酮）。CYP2D6具有遗传多态性，4-10%的高加索人由于遗传了两个非功能性等位基因而缺乏CYP2D6活性（代谢不良）。我们通过基因分型（CYP2D6*3和CYP2D6*4缺陷突变等位基因）对符合或不符合口服阿片类药物依赖DSM标准的白种人进行检测，以确定口服阿片类药物激活失败是否是阿片类药物依赖的保护因素。在阿片类药物（+/-吸烟）依赖的受试者中，我们没有发现代谢不良者。相比之下，非药物依赖对照组和多药物依赖对照组的不良代谢频率分别为4%和6.5%。口服阿片类药物依赖人群中代谢不良者的代表性不足（Fisher精确检验，p <或= 0.05）表明CYP2D6缺陷基因型是口服阿片类药物依赖的药理学保护因素（估计优势比为0.70）。这是第一次研究和证明遗传决定的P450代谢差异影响物质依赖风险，我们认为这些差异可能影响其他底物药物依赖风险，并且可能发生在其他遗传可变的P450。
Oral opiates (e.g. codeine, oxycodone, and hydrocodone) are metabolized by cytochrome CYP2D6 to metabolites of increased activity (e.g. morphine, oxymorphone and hydromorphone). CYP2D6 is genetically polymorphic, 4-10% of Caucasians lack CYP2D6 activity (poor metabolizers) due to inheritance of two non-functional alleles. We tested whether the failure to activate oral opiates was a protection factor in opiate dependence by genotyping (CYP2D6*3 and CYP2D6*4 defective mutant alleles) caucasians who met or didn't meet DSM criteria for oral opiate dependence. In opiate (+/- smoking) dependent subjects we found no poor metabolizers. In contrast, the poor metabolizer frequency in never-dependent control and multi-drug dependent comparison groups was 4% and 6.5%, respectively. This under-representation of poor metabolizers (Fisher's exact test, p < or = 0.05) in people dependent on oral opiates suggests that the CYP2D6 defective genotype is a pharmacogenetic protection factor for oral opiate dependence (estimated odds ratio > 7). This is the first investigation and demonstration of differences in genetically determined P450 metabolism influencing risk for substance dependence and we suggest that these differences may influence the risk for dependence of other substrate drugs, and may occur with other genetically variable P450s.