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首页> 外文期刊>Clinical toxicology: the official journal of the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists >CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants
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CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants

机译：CYP2D6基因多态性及其与安非他明，阿片类镇痛药和抗抑郁药中毒的相关性

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Introduction. Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. Objective. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants in humans. Methods. PubMed (up to August 2013) was searched with the following selection criteria: CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amfetamines, opioid analgesics and antidepressants. Amfetamines. While some in vitro studies suggest that CYP2D6-mediated metabolites of 3,4-methylenedioxymethamfetamine (MDMA) are substantially more cytotoxic compared with unchanged MDMA, it is not yet confirmed in human cases of MDMA intoxication that extensive/ultra-rapid CYP2D6 metabolisers could be at higher risk This would also apply to methamfetamine exposure and the related cardiac and central nervous system toxicity. Opioid analgesics. CYP2D6 ultra-rapid metabolisers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. Antidepressants. CYP2D6 poor metabolisers are generally more prone to adverse effects. Among them, the four drugs with the highest level of evidence are amitriptyline, nortriptyline, venlafaxine and fluoxetine. Further data are needed, however, for doxepin and paroxetine, while citalopram adverse effects seem definitely less influenced by CYP2D6 genetic polymorphisms. Conclusions. Either poor or extensive/ultra-rapid CYP2D6 metabolisers may be exposed to toxic effects of amfetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.
机译：介绍。细胞色素P450 2D6（CYP2D6）是细胞色素P450（CYP）超家族的成员，参与临床毒理学中遇到的药物和滥用物质的生物转化。在CYP超家族中，CYP2D6基因被认为是最多态的，因为到目前为止已鉴定出105种以上的等位基因。 CYP2D6遗传多态性有可能影响其底物的毒性。目的。这篇综述将特别关注CYP2D6基因多态性及其与因氨苯丙胺，阿片类镇痛药和抗抑郁药引起的中毒的相关性。方法。用以下选择标准搜索PubMed（截至2013年8月）：CYP2D6 AND（毒理学或中毒或中毒或过量）。在检索到的454条引用文献中，只有46篇论文涉及CYP2D6多态性对由安非他明，阿片类镇痛药和抗抑郁药引起的中毒的影响。安非他命。尽管一些体外研究表明，与未改变的MDMA相比，CYP2D6介导的3,4-亚甲二氧基甲基苯丙胺（MDMA）代谢产物具有更高的细胞毒性，但尚未证实在人类MDMA中毒病例中，广泛的/超快速的CYP2D6代谢产物可能是高危人群这也适用于甲基苯丙胺暴露及相关的心脏和中枢神经系统毒性。阿片类镇痛药。 CYP2D6超快速代谢者更可能遭受可待因和曲马多的不良影响。因此，不依赖于CYP2D6具有治疗活性的阿片类镇痛药（例如吗啡和氢吗啡酮）可能是可待因和曲马多的更好替代品，其局限在于这些药物具有自己的一系列不良反应。抗抑郁药。 CYP2D6弱代谢者通常更容易产生不良反应。其中，证据最充分的四种药物是阿米替林，去甲替林，文拉法辛和氟西汀。但是，对于多塞平和帕罗西汀，还需要进一步的数据，而西酞普兰的不良作用似乎绝对不受CYP2D6遗传多态性的影响。结论CYP2D6代谢酶的不良或广泛/快速代谢都可能暴露于安非他明，阿片类镇痛药和抗抑郁药的毒性作用。在这三类中，证据水平取决于物质，在同一药理学类别中有所不同。

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