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Relevance of non-synonymous CYP2C8 polymorphisms to 13-cis retinoic acid and paclitaxel hydroxylation

Lookup NU author(s): Sophie Rowbotham, Professor Alan Boddy, Dr Christopher Redfern, Dr Gareth Veal, Professor Ann Daly

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Abstract

CYP2C8 has a major role in the metabolism of the anticancer agents 13-cis retinoic acid (13cisRA) and paclitaxel. There is evidence that polymorphisms in the CYP2C8 gene contribute to observed interindividual differences in paclitaxel metabolism. However, no studies have been performed to determine the relevance of CYP2C8 polymorphisms to 13cisRA metabolism. In the current study, the effect of two common nonsynonymous CYP2C8 polymorphisms, CYP2C8*3 (R139K and K399R) and *4 (I264M), on the metabolism of 13cisRA and paclitaxel was examined using an Escherichia coli expression system with coexpression of human cytochrome P450 reductase. No statistically significant differences in the level of 13cisRA 4-hydroxylase activity were associated with either CYP2C8 allelic variant compared with the wild-type CYP2C8.1 enzyme. Furthermore, no differences were observed for the CYP2C8.3 or CYP2C8.4 enzymes with respect to paclitaxel 6α-hydroxylase kinetics compared with wild-type CYP2C8.1. However, when the effects of the individual polymorphisms making up the CYP2C8*3 allele were considered, a significantly lower level of paclitaxel 6α-hydroxylase activity was associated with the K399R enzyme. A lower level of activity was also seen for the R139K enzyme, although this difference was not significant. No differences were observed with respect to 13cisRA 4-hydroxylase activity. We conclude that common CYP2C8 polymorphisms are unlikely to explain reported interindividual variation in 13cisRA or paclitaxel pharmacokinetics.


Publication metadata

Author(s): Rowbotham SE, Boddy AV, Redfern CPF, Veal GJ, Daly AK

Publication type: Article

Journal: Drug Metabolism and Disposition

Year: 2010

Volume: 38

Issue: 8

Pages: 1261-1266

Print publication date: 26/04/2010

ISSN (print): 0090-9556

ISSN (electronic): 1521-009X

Publisher: American Society for Pharmacology and Experimental Therapeutics

URL: http://dx.doi.org/10.1124/dmd.109.030866

DOI: 10.1124/dmd.109.030866


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