title: Evaluation of the effects of cytochrome P450 nonsynonymous single-nucleotide polymorphisms on tanshinol borneol ester metabolism and inhibition potential.
abstract: Nonsynonymous single-nucleotide polymorphisms (nsSNPs) in cytochrome P450 (P450) genes may affect drug metabolism and drug-drug interactions (DDIs), potentially leading to adverse drug reactions. Functional characterization of the nsSNPs in P450 genes is important to help us understand the impact of genetic factors on P450-mediated drug metabolism and DDIs. To evaluate the effects of P450 nsSNPs on the metabolism and inhibition potential of a candidate drug, tanshinol borneol ester (DBZ), we obtained and experimentally validated eight yeast-expressed human P450 isoforms and their nsSNP variants and tested DBZ using these recombinant P450 enzymes. The results suggested that CYP2C8 is the major enzyme responsible for DBZ metabolism. In addition, compared with prototypic CYP2C8, the allelic variant, CYP2C8.3, produced a 54% decrease in the intrinsic clearance of DBZ. The inhibitory potency of DBZ toward CYP3A4 was greater than that toward other P450 isoforms, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Moreover, the inhibitory potency toward three CYP3A4 allelic variants, CYP3A4.2, CYP3A4.12, and CYP3A4.16, was reduced 2- to 10-fold relative to prototype CYP3A4. These results provide useful information for understanding the influence of P450 genetic polymorphisms on DBZ metabolism and may help to design future clinical trials of DBZ. Our results suggest applications for in vitro P450 assays both for basic research in pharmacogenomics and for drug development.
authors.affiliation: National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, No. 229, North Taibai Road, Xi'an 710069, China.
authors.forename: Duan
authors.initials: D
authors.lastname: Liu
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Gao
authors.forename: Huijuan
authors.initials: H
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zi
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
authors.forename: Ruimin
authors.initials: R
authors.lastname: Zhou
authors.forename: Yefei
authors.initials: Y
authors.lastname: Nan
authors.forename: Shixiang
authors.initials: S
authors.lastname: Wang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zheng
authors.forename: Juanli
authors.initials: J
authors.lastname: Zhu
authors.forename: Yali
authors.initials: Y
authors.lastname: Cui
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
mesh_terms: D001892:Camphanes / Q000378:metabolism* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007773:Lactates / Q000378:metabolism* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide
chemical_list: C554681:1,7,7-trimethylbicyclo(2.2.1)heptan-2-yl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate; D001892:Camphanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007773:Lactates; D003577:Cytochrome P-450 Enzyme System