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Rapid CommunicationShort Communication

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cis Retinoic Acid and Paclitaxel Hydroxylation

Sophie E. Rowbotham, Alan V. Boddy, Chris P. F. Redfern, Gareth J. Veal and Ann K. Daly
Drug Metabolism and Disposition August 2010, 38 (8) 1261-1266; DOI: https://doi.org/10.1124/dmd.109.030866
Sophie E. Rowbotham
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Alan V. Boddy
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Chris P. F. Redfern
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Gareth J. Veal
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Ann K. 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.

Footnotes

  • This work was supported by Cancer Research UK.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.030866.

  • ABBREVIATIONS:

    13cisRA
    13-cis retinoic acid
    P450
    cytochrome P450
    PCR
    polymerase chain reaction
    LCMS
    liquid chromatography-mass spectrometry.

  • Received November 4, 2009.
  • Accepted April 26, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Rapid CommunicationShort Communication

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cis Retinoic Acid and Paclitaxel Hydroxylation

Sophie E. Rowbotham, Alan V. Boddy, Chris P. F. Redfern, Gareth J. Veal and Ann K. Daly
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1261-1266; DOI: https://doi.org/10.1124/dmd.109.030866

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Rapid CommunicationShort Communication

Relevance of Nonsynonymous CYP2C8 Polymorphisms to 13-cis Retinoic Acid and Paclitaxel Hydroxylation

Sophie E. Rowbotham, Alan V. Boddy, Chris P. F. Redfern, Gareth J. Veal and Ann K. Daly
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1261-1266; DOI: https://doi.org/10.1124/dmd.109.030866
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