Yilmaz N, Erbağci A B, Aynacioğlu A S
Department of Biochemistry and Clinical Biochemistry, Faculty of Medicine, University of Gaziantep, Turkey.
Acta Biochim Pol. 2001;48(3):775-82.
Substrates for CYP2C9 include fluoxetine, phenytoin, warfarin, losartam and numerous nonsteroidal anti-inflammatory drugs. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino-acid residues 144 Arg/Cys and 359 Ile/Leu of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, the frequency of this allele is, however, rather low. Consistently with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. The polymorphic enzyme CYP2C9 takes part in the metabolism of alkylating agents and polycyclic aromatic hydrocarbons like benzo(a)pyrene, a carcinogen present in tobacco smoke. Although the impact of impaired enzyme activity in metabolism of carcinogens and procarcinogens has not been fully defined, an association of CYP2C9 variant alleles to DNA adduct levels in lung tissues as well as to lung cancer risk have been reported. In this study 64 healthy subjects (44M/22F) were analysed for CYP2C9 genotype with PCR-RFLP and for serum carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CA 19-9, CA 15-3, ferritin, IL-6, IL-8 concentrations by chemiluminescence or electrochemiluminescence methods. CYP2C91 was found to be the most prevalent allele and CYP2C91/CYP2C9*1 was the most frequent genotype represented in 64% of the population in southeastern Anatolia (Gaziantep). Although slight differences in serum tumour marker and cytokine concentrations were observed for CYP2C9 genotypes the differences were statistically insignificant (P > 0.05). This could be due to the complexity of the role of CYP2C9 in benzo(a)pyrene metabolism as well as from other contributing factors like interindividual variability of diverse enzymes participating in the same metabolic pathway, unequal expression of the variant alleles and differences in exposure to carcinogens. However, determination of CYP2C9 phenotypes in a larger group of subjects might clarify these slight differences.
细胞色素P450 2C9（CYP2C9）的底物包括氟西汀、苯妥英、华法林、氯沙坦以及众多非甾体抗炎药。CYP2C9基因编码区的多态性在CYP2C9蛋白的第144位氨基酸残基（Arg/Cys）和第359位氨基酸残基（Ile/Leu）处产生变异。Leu359纯合个体对大多数CYP2C9底物的代谢能力显著降低，不过该等位基因的频率相当低。与遗传和其他因素对酶活性的调节一致，原型CYP2C9底物的消除和/或剂量需求存在广泛的个体间差异。多态性酶CYP2C9参与烷基化剂和多环芳烃（如烟草烟雾中的致癌物苯并(a)芘）的代谢。尽管酶活性受损对致癌物和前致癌物代谢的影响尚未完全明确，但已有报道称CYP2C9变异等位基因与肺组织中的DNA加合物水平以及肺癌风险相关联。在本研究中，采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对64名健康受试者（44名男性/22名女性）的CYP2C9基因型进行分析，并采用化学发光或电化学发光方法检测血清癌胚抗原（CEA）、甲胎蛋白（AFP）、CA 19-9、CA 15-3、铁蛋白、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）的浓度。发现CYP2C91是最常见的等位基因，CYP2C91/CYP2C9*1是最常见的基因型，在安纳托利亚东南部（加济安泰普）64%的人群中出现。尽管观察到CYP2C9基因型在血清肿瘤标志物和细胞因子浓度上存在轻微差异，但这些差异无统计学意义（P>0.05）。这可能是由于CYP2C9在苯并(a)芘代谢中的作用复杂，以及其他一些影响因素，如参与同一代谢途径的多种酶的个体间差异、变异等位基因的不等表达以及致癌物暴露的差异。然而，在更大规模的受试者群体中测定CYP2C9表型可能会阐明这些细微差异。
