Fekete Ferenc, Mangó Katalin, Minus Annamária, Tóth Katalin, Monostory Katalin
Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, Hungary.
Doctoral School of Biology and Institute of Biology, Eötvös Loránd University, Pázmány Péter Sétány 1/A, H-1117 Budapest, Hungary.
Pharmaceutics. 2022 Feb 27;14(3):532. doi: 10.3390/pharmaceutics14030532.
CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A21F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A21F, CYP1A21L, CYP1A21M, CYP1A21V, CYP1A21W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype−phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.
细胞色素P450 1A2（CYP1A2）是肝脏中含量最丰富的细胞色素P450酶之一，参与多种药物和致癌化合物的代谢。关于CYP1A2基因多态性对酶活性影响的数据高度不一致；因此，在人类肝脏组织和属于高加索人群的精神病患者中，研究了CYP1A2基因变异（-3860G>A、-2467delT、-739T>G、-163C>A、2159G>A）对mRNA表达以及对CYP1A2具有选择性的非那西丁O-脱烷基作用的影响。CYP1A21F被认为与CYP1A2的高诱导性有关，通常通过-163C>A多态性的存在来鉴定；然而，我们证明-163C>A存在于几种单倍型（CYP1A21F、CYP1A21L、CYP1A21M、CYP1A21V、CYP1A21W）中，因此，CYP1A2*1F是一种比在高加索人群中报道的更为罕见的等位基因变体（0.4%）。值得注意的是，发现-163C>A多态性既不会导致CYP1A2的mRNA增加，也不会导致其活性增加。此外，肝脏CYP1A2活性与肝脏或白细胞mRNA表达相关，而不是与CYP1A2的基因多态性相关。考虑非基因表型转化因素（与CYP1A2特异性抑制剂/诱导剂的联合用药、吸烟以及非特异性因素，包括阿莫西林+克拉维酸治疗或长期饮酒）并不能显著改善基因型-表型估计。总之，CYP1A2基因分型不适用于预测CYP1A2功能；然而，白细胞中的CYP1A2 mRNA表达可以反映患者的CYP1A2代谢能力。
