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Research ArticleArticle

Metabolism of Vinyl Chloride: Destruction of the Heme of Highly Purified Liver Microsomal Cytochrome P-450 by a Metabolite

F. PETER GUENGERICH and THOMAS W. STRICKLAND
Molecular Pharmacology November 1977, 13 (6) 993-1004;
F. PETER GUENGERICH
Department of Biochemistry and Center in Environmental Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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THOMAS W. STRICKLAND
Department of Biochemistry and Center in Environmental Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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Abstract

The NADPH-dependent, vinyl chloride-mediated destruction of cytochrome P-450 was demonstrated in rat liver microsomes and in highly purified reconstituted enzyme systems containing NADPH-cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4) and cytochrome P-450. This loss of cytochrome P-450 could be attributed to heme destruction, but not to lipid peroxidation or binding of electrophiles to free sulfhydryl groups. The system required all components necessary for mixed-function oxidation, including molecular oxygen, and was inhibited by carbon monoxide, suggesting strongly that oxidative metabolism of vinyl chloride by cytochrome P-450 is necessary for the observed destruction. The NADPH-cytochrome P-450 reductase-catalyzed destruction of free and cytochrome P-450-bound heme was also observed in reconstituted systems in the absence of vinyl chloride. Inhibition experiments with carbon monoxide and catalase suggest that the vinyl chloride-mediated destruction of cytochrome P-450 heme differs from these processes. Two proposed metabolites of vinyl chloride, vinyl chloride epoxide and 2-chloroacetaldehyde, do not appear to be responsible for the heme destruction. Evidence for the involvement of free radicals could not be demonstrated when the reaction was examined by EPR spectroscopy or when attempts were made to inhibit cytochrome P-450 destruction with radical-trapping agents.

ACKNOWLEDGMENT We wish to express our gratitude to Dr. T. Martin, Department of Chemistry, Vanderbilt University, for his help with the EPR spectroscopy.

  • Copyright © 1977 by Academic Press, Inc.

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Molecular Pharmacology
Vol. 13, Issue 6
1 Nov 1977
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Research ArticleArticle

Metabolism of Vinyl Chloride: Destruction of the Heme of Highly Purified Liver Microsomal Cytochrome P-450 by a Metabolite

F. PETER GUENGERICH and THOMAS W. STRICKLAND
Molecular Pharmacology November 1, 1977, 13 (6) 993-1004;

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Research ArticleArticle

Metabolism of Vinyl Chloride: Destruction of the Heme of Highly Purified Liver Microsomal Cytochrome P-450 by a Metabolite

F. PETER GUENGERICH and THOMAS W. STRICKLAND
Molecular Pharmacology November 1, 1977, 13 (6) 993-1004;
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