Abstract

One hour after the intraperitoneal administration of CHCl3, CBrCl3, or CCl4 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 CHCl3, CBrCl3, and CCl4 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), CBrCl3, and CCl4. After the administration of CHCl3, CBrCl3, and CCl4, 2.89, 0.64, or 0.11 mumol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that 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 amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.