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Formation of Carbonyl Chloride in Carbon Tetrachloride Metabolism by Rat Liver in Vitro¹

Feis Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

In order to identify intermediates of CCl₄ metabolism, whole, suitably fortified rat liver homogenates were incubated with ¹⁴CCl₄ in the presence and absence of "pools" of unlabeled suspected intermediates. In the presence of NADH or NADPH, incorporation of radioactivity was rapid and substantial in CO₂, lipid, protein, and the acid-soluble fraction. It was not influenced by the presence of large pools of unlabeled chloroform or formate, thus excluding these substances as obligatory intermediates. However, when incubated with L-cysteine, radioactivity incorporation in the acid-soluble fraction was almost doubled, and about one-third of the radioactivity of this fraction was identified as 2-oxothiazolidine 4-carboxylic acid. This substance is formed chemically by condensation of cysteine with carbonyl chloride and has been identified previously by others as a product of chloroform metabolism by liver microsomes in the presence of L-cysteine. Based on current knowledge of CCl₄ metabolism, the following aerobic pathway is envisioned: microsomal cleavage to Cl^– and ·CCl₃ and oxidation of the latter to the unstable intermediate, Cl₃COH, which loses HCl to yield COCl₂. COCl₂ is likely to be the major source of CO₂ from CCl₄ but is probably not the intermediate that binds to lipid and protein. The addition of glutathione had no effect on CCl₄ metabolism in rat liver homogenate, suggesting that glutathione S-transferases, which catalyze other dehalogenation reactions, do not play a role in CCl₄ metabolism.

¹ This work was aided by Grants BC-74 from the American Cancer Society and CA-10916 and CA-12227 from the National Cancer Institute, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 3/21/79. Accepted 6/25/79.