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Research ArticleArticle

Specific Dehydrogenation of 3-Methylindole and Epoxidation of Naphthalene by Recombinant Human CYP2F1 Expressed in Lymphoblastoid Cells

Diane L. Lanza, Erin Code, Charles L. Crespi, Frank J. Gonzalez and Garold S. Yost
Drug Metabolism and Disposition July 1999, 27 (7) 798-803;
Diane L. Lanza
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Erin Code
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Charles L. Crespi
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Frank J. Gonzalez
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Garold S. Yost
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Abstract

3-Methylindole (3MI) is a naturally occurring pulmonary toxin that requires metabolic activation. Previous studies have shown that 3MI-induced pneumotoxicity resulted from cytochrome P-450-catalyzed dehydrogenation of 3MI to an electrophilic methylene imine (3-methyleneindolenine), which covalently bound to cellular macromolecules. Multiple cytochrome P-450s are capable of metabolizing 3MI to several different metabolites, including oxygenated products. In the present study, the role of human CYP2F1 in the metabolism of 3MI was examined to determine whether it catalyzes dehydrogenation rather than hydroxylation or ring oxidation. Metabolism was examined using microsomal fractions from human lymphoblastoid cells that expressed the recombinant human CYP2F1 P-450 enzyme. Expression of CYP2F1 in the lymphoblastoid cells proved to be an appropriate expression system for this enzyme. Products were analyzed using HPLC and the mercapturate, 3-[(N-acetylcystein-S-yl)methyl]indole, of the reactive intermediate was identified and quantified. Product analysis showed that human CYP2F1 efficiently catalyzed the dehydrogenation of 3MI to the methylene imine without detectable formation of indole-3-carbinol or 3-methyloxindole. High substrate concentrations of 3MI strongly inhibited production of the dehydrogenated product, a result that may indicate the existence of mechanism-based inhibition of CYP2F1 by 3MI. Recombinant CYP2F1 demonstrated remarkable selectivity for the bioactivation of 3MI to the putative dehydrogenated reactive electrophile. Bioactivation of naphthalene to its pneumotoxic epoxide by CYP2F1 was also demonstrated.

Footnotes

  • Send reprint requests to: Dr. Garold S. Yost, Department of Pharmacology & Toxicology, 30 South 2000 East, Room 201, University of Utah, Salt Lake City, UT 84112-5820. E-mail:gyost{at}deans.pharm.utah.edu

  • This project was supported by National Institutes of Health Grants P42-ES-04675–10 (Gentest) and HL13645 (University of Utah).

  • Abbreviations used are::
    3MI
    3-methylindole
    NAC
    N-acetylcysteine
    3MINAC
    3-[(N-acetylcystein-S-yl)methyl]indole
    • Received December 31, 1998.
    • Accepted April 12, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (7)
Drug Metabolism and Disposition
Vol. 27, Issue 7
1 Jul 1999
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Research ArticleArticle

Specific Dehydrogenation of 3-Methylindole and Epoxidation of Naphthalene by Recombinant Human CYP2F1 Expressed in Lymphoblastoid Cells

Diane L. Lanza, Erin Code, Charles L. Crespi, Frank J. Gonzalez and Garold S. Yost
Drug Metabolism and Disposition July 1, 1999, 27 (7) 798-803;

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Research ArticleArticle

Specific Dehydrogenation of 3-Methylindole and Epoxidation of Naphthalene by Recombinant Human CYP2F1 Expressed in Lymphoblastoid Cells

Diane L. Lanza, Erin Code, Charles L. Crespi, Frank J. Gonzalez and Garold S. Yost
Drug Metabolism and Disposition July 1, 1999, 27 (7) 798-803;
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