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

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.