Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 37

The CYP2D6 polymorphism has been studied extensively, and 139 major variants have been cataloged in the PharmVar. The most common null allele in the Caucasian population is CYP2D6*4, accounting for the majority (70–90%) of the poor metabolizer phenotype [41, 73]. CYP2D6*4 carriers all have a 1847G>A mutation, causing splicing defect and no protein expression in the liver. The CYP2D6*10 allele is most commonly found in Asians [74]. Double SNP mutations 100C>T (P34S) and 4181G>C (S486T) render the protein unstable. In the African population the CYP2D6*17 allele has the highest frequency [75]. Triple mutations, 1022C>T (T107I), 2851C>T (R296C), and 4181G>C (S486T), lead to a structural change in the active site, which alters the substrate specificity. The pharmacogenetic impact of CYP2D6 on opioid drugs has been demonstrated [76]. Tramadol, for example, is bioactivated by CYP2D6 into active metabolite O‐desmethyltramadol [77]. Poor metabolizers are insensitive to opioids and have much lower analgesic response [78]. In contrast, ultrarapid metabolizers with duplicated CYP2D6 genes show significantly increased efficiency in converting opioid prodrugs such as tramadol and codeine into active metabolites, which could cause opioid overdose [79]. The impact of CYP2D6 polymorphism is not limited to opioid drugs but covers a spectrum of clinical drugs. It might be a contributing factor to the hepatoxicity of perhexiline and trazodone [80, 81]. The case of a CYP2D6 poor metabolizer with perhexiline‐associated DILI has been reported. Significantly higher plasma Cmax of m‐chloro, 4‐phenylpiperazine, a hepatotoxic metabolite of trazodone, was observed in poor metabolizers in comparison to extensive metabolizers. However, the pharmacogenetic association has not been confirmed.