title: Gene polymorphisms and contents of cytochrome P450s have only limited effects on metabolic activities in human liver microsomes.
abstract: Extensive inter-individual variations in pharmacokinetics are considered as a major reason for unpredictable drug responses. As the most important drug metabolic enzymes, inter-individual variations of cytochrome P450 (CYP) activities are not clear in human liver. In this paper, metabolic activities, gene polymorphisms and protein contents of 10 CYPs were determined in 105 human normal liver microsomes. The results indicated substantial inter-individual variations in CYP activities, with the greatest being CYP2C19 activity (>600-fold). Only half of 10 CYP isoforms and 26 gene polymorphism sites had limited effects on metabolic activities, such as CYP2A6, CYP2B6, CYP2C9, CYP2D6 and CYP3A4/5, others had almost no effects. Compared with their respective wild type, Km, Vmax, and CLint decreased by 51.6%, 88.7% and 70.7% in CYP2A6*1/*4 genotype, Vmax and CLint decreased by 32.8% and 60.2% in CYP2C9*1/*3 genotype, Km increased by 118.4% and CLint decreased by 65.2% in CYP2D6 100TT genotype, respectively. Moreover, there were only 4 CYP isoforms, CYP1A2, CYP2A6, CYP2E1 and CYP3A5, which had moderate or weak correlations between Vmax values and corresponding contents. In conclusions, the genotypes and contents of some CYPs have only limited effects on metabolic activities, which imply that there are other more important factors to influence inter-individual variations.
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Linjing
authors.initials: L
authors.lastname: Jia
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Bao
authors.initials: B
authors.lastname: Sun
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Cui
authors.affiliation: Institute of Clinical Pharmacology, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, People's Republic of China. Electronic address: qiaohl@zzu.edu.cn.
authors.forename: Hailing
authors.initials: H
authors.lastname: Qiao
mesh_terms: D000328:Adult; D000368:Aged; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; Drug metabolism; Gene polymorphism; Individual variations; Protein content