Hepatoprotection by dimethyl sulfoxide - III. Role of inhibition of the bioactivation and covalent binding of chloroform

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl3)-induced liver injury in the naive rat even whe n administered 24 h after the toxicant, These studies were undertaken to de termine if the protective action by late administration of DMSO is due to a n inhibition of the bioactivation of CHCl3. This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole ( ABT) to DMSO for their protective efficacy when administered 24 h after CHC l3 exposure, In addition, (CHCl3)-C-14 was utilized to measure the effect o f DMSO and ABT on the covalent binding of CHCl3 in the liver following thei r late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 m l/kg CHCl3 po. Twenty-four hours later, they received ip injection of 2 ml/ kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT, Plasma ALT activities and quantita tion of liver injury by light microscopy at 48 h after CHCl3 dosing indicat ed that all three treatments were equally effective at protecting the liver . A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administrati on. Therefore, in the radiolabel studies, rats were killed 24-34 h after re ceiving 0.75 ml/kg CHCl3 (30 mu Ci/kg (CHCl3)-C-14) po. Treatment with ABT at 24 h after (CHCl3)-C-14 dosing decreased the covalent binding of C-14 to hepatic protein by 35% and reduced the amount of C-14 in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affe ct any of these parameters. The lack of effect by late administration of DM SO on the covalent binding of CHCl3 would indicate that DMSO may offer prot ection by mechanisms other than inhibition of the bioactivation of CHCl3, T hese studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the ant idotes are administered a number of hours after the initial exposure. (C) 2 000 Academic Press.