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Molecular Pharmacology, Vol 14, 1099-1106, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Accelerated Conversion of Heme to Bile Pigments Caused in the Liver by Carbon Disulfide and Other Sulfur-containing Chemicals

J. JÄRVISALO 1, A. H. GIBBS 1, and F. DE MATTEIS 1

1 Biochemical Pharmacology Section, Toxicology Unit, Medical Research Council Laboratories, Carshalton SM5 4EF, Surrey, U.K.

After CS2 administration a slight loss of heme was demonstrated from the microsomal fraction of rat liver, and when the microsomal heme was prelabeled with 5-amino[4-14C]levulinate, a loss of heme radioactivity from the microsomes was observed after CS2 treatment with accumulation of heme radioactivity in the cell sap. The conversion in vivo of 5-amino[4-14C]levulinate into bile bilirubin and the activity of liver heme oxygenase were both stimulated by CS2 treatment. Phenobarbital pretreatment of the rats, prior to CS2 administration, potentiated the stimulation of heme oxygenase caused by CS2, whereas cycloheximide pretreatment completely prevented it. A stimulation of liver heme oxygenase was also found after administration of diethylphenylphosphorothionate, pentothal, and phenylthiourea, whereas the oxygen-containing analogues of the last two drugs were inactive. It is concluded that the accelerated liver heme conversion to bile pigments caused by CS2, pentothal, and other sulfur-containing drugs is related to their metabolism by oxidative desulfuration and ensuing microsomal toxicity: the damage of the apoprotein of cytochrome P-450 may result in a reduced affinity for heme, with more liver heme being available for degradation.

Note:
ACKNOWLEDGMENTS We thank Dr. W. N. Aldridge for providing a sample of diethylphenylphosphorothionate.

Submitted on March 28, 1978
Accepted on June 8, 1978




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S. W. Ryter, J. Alam, and A. M. K. Choi
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Physiol Rev, April 1, 2006; 86(2): 583 - 650.
[Abstract] [Full Text] [PDF]


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