THE FORMATION OF DIGLUTATHIONYL DITHIOCARBONATE AS A METABOLITE OF CHLOROFORM, BROMOTRICHLOROMETHANE, AND CARBON-TETRACHLORIDE

Abstract

At 1 h after the i.p. administration of CHCl3, CBrCl3 or CCl4 to phenobarbital(PB)-treated rats, hepatic GSH [glutathione] levels decreased to 30, 59 and 88% of control levels, respectively; after 4 h, the GSH levels had returned to 46, 65 and 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 CHCl3, CBrCl3 and CCl4 to GSCOSG was 180, 58 and 8 nmol/mg of protein per 15 min, respectively. The GSCOSG was identified in bile by 13C-NMR spectroscopy and HPLC [high pressure liquid chromatography] as an in vivo metabolite of CHCl3, CBrCl3 and CCl4. After the administration of CHCl3, CBrCl3 and CCl4, 2.89, 0.64 or 0.11 .mu.mol of GSCOSG, respectively, were excreted in 6 h. CHCl3, CBrCl3 and CCl4 are metabolized in vitro and in vivo to phosgene (COCl2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl2 may be responsible at least in part for the GSH-depleting properties of CHCl3, CBrCl3 and CCl4, inasmuch as the relative amount of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.