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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes

Jennifer B. Dennison, David R. Jones, Jamie L. Renbarger and Stephen D. Hall
Journal of Pharmacology and Experimental Therapeutics May 2007, 321 (2) 553-563; DOI: https://doi.org/10.1124/jpet.106.118471
Jennifer B. Dennison
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David R. Jones
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Jamie L. Renbarger
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Stephen D. Hall
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Abstract

Vincristine is preferentially metabolized to a secondary amine, M1, by CYP3A5 with a 9- to 14-fold higher intrinsic clearance than CYP3A4 using cDNA-expressed enzymes. The genetically polymorphic expression of CYP3A5 may contribute to interindividual variability in vincristine efficacy and toxicity. The current study quantifies the contribution of cytochromes P450 (P450s), including CYP3A4 and CYP3A5, to vincristine metabolism with a bank of human liver microsomes (HLMs). M1 was the major metabolite formed with HLMs, and selective chemical inhibition of P450s confirmed that CYP3A was the major metabolizing subfamily. The liver tissues were genotyped for low expression alleles, CYP3A5*3,*6, and *7, and the HLMs were phenotyped for CYP3A4 and CYP3A5 expression by Western blot. Testosterone 6β-hydroxylation and itraconazole hydroxylation were used to quantify CYP3A4 activity in the HLMs. For each CYP3A5 high expresser (n = 10), the rate of M1 formation from vincristine due to CYP3A5 was quantified by subtracting the CYP3A4 contribution as determined by linear regression with CYP3A5*3/*3 samples. For CYP3A5 high expressers, the contribution of CYP3A5 to the metabolism of vincristine was 54 to 95% of the total activity, and the rate of M1 formation mediated by CYP3A5 correlated with CYP3A5 protein content (r2 = 0.95). Selective inhibition of CYP3A4 demonstrated that the M1 formation rate with CYP3A5 high expressers was differentially inhibited based on CYP3A4 activity. Using median values, the estimated hepatic clearances were 5-fold higher for CYP3A5 high expressers than low expressers. We conclude that polymorphic expression of CYP3A5 may be a major determinant in the P450-mediated clearance of vincristine.

Footnotes

  • This study was funded by National Institutes of Health Grant 1 K23 RR019956-01 and a Pharmaceutical Research and Manufacturers of America Foundation Pharmacology predoctoral fellowship.

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

  • doi:10.1124/jpet.106.118471.

  • ABBREVIATIONS: P450, cytochrome P450; HLM, human liver microsome; VCR, vincristine; VLB, vinblastine; VRL, vinorelbine; DDC, diethyldithiocarbamic acid; TST, testosterone; ITZ, itraconazole; OH-ITZ, hydroxyitraconazole; MeO-ITZ, methoxyitraconazole; HPLC, high-performance liquid chromatography; LC, liquid chromatography; MS/MS, tandem mass spectrometry; CsA, cyclosporin A; CL, clearance.

    • Received December 12, 2006.
    • Accepted January 31, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 387 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 387, Issue 3
1 Dec 2023
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes

Jennifer B. Dennison, David R. Jones, Jamie L. Renbarger and Stephen D. Hall
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 553-563; DOI: https://doi.org/10.1124/jpet.106.118471

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes

Jennifer B. Dennison, David R. Jones, Jamie L. Renbarger and Stephen D. Hall
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 553-563; DOI: https://doi.org/10.1124/jpet.106.118471
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