Molecular Pharmacology, Vol 10, 849-854, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Covalent Binding of Sulfur to Microsomes and Loss of Cytochrome P-450 during the Oxidative Desulfuration of Several Chemicals

¹ Biochemical Mechanisms Section, Medical Research Council Toxicology Unit, Carshalton, Surrey, England

When liver microsomes from phenobarbitone-treated rats are incubated with carbon disulfide, a marked loss of cytochrome P-450 is observed only when NADPH is present. By employing ¹⁴C- and ²⁵S-labeled CS₂, it has been found that in the presence of NADPH labeled sulfur becomes covalently bound to microsomes: The binding of ³⁵S exceeds that of ¹⁴C, indicating that sulfur itself becomes bound. A loss of cytochrome P-450 is also seen when parathion, phenylthiourea, or 1-naphthylisothiocyanate is incubated with liver microsomes in the presence of NADPH, whereas the oxygen-containing analogues of these compounds are all inactive. It is concluded that reactive sulfur liberated during the oxidative desulfuration of several chemicals may become bound to cellular components and initiate toxic changes in the liver. This may account not only for the loss of cytochrome P-450 but also for the centrilobular hydropic degeneration seen in vivo.

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ACKNOWLEDGMENTS The author would like to thank Mr. A. H. Gibbs and Mr. T. W. Poole for skilled technical assistance.