The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride

L. R. Pohl, R. V. Branchflower, R. J. Highet, J. L. Martin, D. S. Nunn, T. J. Monks, J. W. George, J. A. Hinson

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Abstract

One hour after the intraperitoneal administration of CHCl 3, CBrCl 3, or CCl 4 to phenobarbital (PB)-treated rats, hepatic GSH levels decreased to 30, 59, and 88% of control levels, respectively; after 4 hr, the GSH levels had returned to 46, 65, 99%, respectively, of control levels. When incubated for 15 min in air with rat liver microsomes from PB-treated rats, a NADPH-generating system, and GSH (5 mM), all of the compounds were converted to diglutathionyl dithiocarbonate (GSCOSG). The rate of conversion of CHCl 3, CBrCl 3, and CCl 4 to GSCOSG was 180, 58, and 8 nmol per mg of protein per 15 min, respectively. The GSCOSG was also identified in bile by 13C-NMR spectroscopy and HPLC as an in vivo metabolite of CHCl 3, CBrCl 3, and CCl 4. After the administration of CHCl 3, CBrCl 3, and CCl 4, 2.89, 0.64, or 0.11 μmol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that CHCl 3, CBrCl 3, and CCl 4 are metabolized in vitro and in vivo to phosgene (COCl 2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl 2 may be responsible at least in part for the GSH-depleting properties of CHCL 3, CBrCl 3, and CCl 4, inasmuch as the relative amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.

Original languageEnglish (US)
Pages (from-to)334-339
Number of pages6
JournalDrug Metabolism and Disposition
Volume9
Issue number4
StatePublished - Nov 9 1981

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Pohl, L. R., Branchflower, R. V., Highet, R. J., Martin, J. L., Nunn, D. S., Monks, T. J., George, J. W., & Hinson, J. A. (1981). The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. Drug Metabolism and Disposition, 9(4), 334-339.