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Vol. 27, Issue 7, 798-803, July 1999
Department of Pharmacology and Toxicology, University of Utah, Salt
Lake City, Utah (D.L.L., G.S.Y.); Gentest Corporation, Woburn,
Massachusetts (E.C., C.L.C.); and Laboratory of Metabolism, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland
(F.J.G.)
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.
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