Evaluation of the Effects of Cytochrome P450 Nonsynonymous Single-Nucleotide Polymorphisms on Tanshinol Borneol Ester Metabolism and Inhibition Potential

• Published in: Drug metabolism and disposition Vol. 38; no. 12; pp. 2259 - 2265
• Main Authors: Liu, Duan, Gao, Yiwen, Wang, Huijuan, Zi, Jing, Huang, He, Ji, Jing, Zhou, Ruimin, Nan, Yefei, Wang, Shixiang, Zheng, Xiaohui, Zhu, Juanli, Cui, Yali, Chen, Chao
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.12.2010
• Subjects: Biological and medical sciences; Bornanes - metabolism; Bornanes - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - genetics; Enzyme Inhibitors - pharmacology; Humans; Lactates - metabolism; Lactates - pharmacology; Medical sciences; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Ester; Evaluation; Terpene; Genetic variability; Enzyme; Borneol; Cytochrome P450; Genotype; Inhibitor; Single nucleotide polymorphism; Pharmacokinetics; Metabolism
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.110.034439

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.