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Evaluation of a role for phosgene production in the hepato toxic mechanism of action of carbon tetra chloride and bromotrichloro methane

Toxicology & Applied Pharmacology 66(2): 172-181
Evaluation of a role for phosgene production in the hepato toxic mechanism of action of carbon tetra chloride and bromotrichloro methane
During aerobic incubations of rat liver microsomes containing a NADPH generating system, 1.54% of added 14CCl4 and 3.05% of added bromotrichloromethane (CBrCl3) could be recovered as the 2-oxothiazolidene-4-carboxylic acid derivative of phosgene. Actual nanomolar quantities of phosgene formed were very small in comparison to input concentrations of phosgene necessary to depress microsomal cytochrome P-450 and glucose-6-phosphatase. Cysteine had no statistically significant effect on covalent binding of 14CCl4 metabolites to either microsomal lipids or proteins. The presence of cysteine had no protective effect against loss of cytochrome P-450, glucose-6-phosphatase or the capacity of microsomes to sequester Ca2+ all of which losses occur in vitro as a result of the metabolism of either CCl4 or CBrCl3. The low level of phosgene production, the lack of any effect of cysteine on the degree of covalent binding of CCl4 metabolites, the failure of cysteine to afford any protection against CCl4- or CBrCl3-dependent loss of microsomal enzyme activity and the relative ineffectiveness of phosgene itself as a microsomal poison argue against the possibility that formation of phosgene plays a significant role in the liver injury resulting from CCl4 or CBrCl3 intoxication. These experiments, do not rule out the possibility that some phosgene production and subsequent toxicological action may occur in a hydrophobic microenvironment of the endoplasmic reticulum.

Accession: 005395652

PMID: 7164096

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