人类细胞色素P450 2 d6多态性及其临床意义:第一部分。
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周科幻
人类细胞色素P450 2 d6多态性及其临床意义:第一部分。
48 Pharmacokinet。2009; (11): 689 - 723。doi: 10.2165 / 11318030-000000000-00000。
- PubMed ID
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19817501 (在PubMed]
- 文摘
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细胞色素P450 (CYP) 2 d6的调查CYP与基因多态性,但只占一小部分肝CYP(约2 - 4%)。有一个大的个人间CYP2D6酶活性的变化。这种酶在很大程度上是non-inducible和代谢目前大约25%的药物。典型基质CYP2D6在很大程度上是亲脂性的基地,包括一些抗抑郁药,抗精神病药物,那儿beta-adrenoceptor拮抗剂(β受体阻断剂)和阿片类药物止吐药。CYP2D6活动范围大大在人口,包括超速的代谢(嗯),广泛的代谢(EMs),中间代谢(IMs)和穷人的代谢(PMs)。有相当大的可变性CYP2D6等位基因分布在不同的民族,导致变量的PMs的百分比,在某一特定人群内的人口的IMs, EMs,嗯。到目前为止,74个等位变异和一系列subvariants CYP2D6基因的报道和等位基因的数量仍在增长。其中包括功能齐全的等位基因的等位基因,降低功能和零(非功能性)等位基因,传达各种各样的酶活性,从没有超速的代谢底物的活动。因此,药物不良反应或缺乏药物作用可能发生如果应用标准剂量。等位基因* 10 * 36和* 41 * 17日产生substrate-dependent减少活动。 Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent beta-blocker than its metabolites and the beta-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this beta-blocker, while such an effect is lesser or marginal in other beta-blockers. Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.
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