Hepatoprotection by Dimethyl Sulfoxide

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl sub(3))-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl sub(3). 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 CHCl sub(3) exposure. In addition, super(14)CHCl sub(3) was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl sub(3) in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl sub(3) 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 quantitation of liver injury by light microscopy at 48 h after CHCl sub(3) dosing indicated 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 administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl sub(3) (30 mu Ci/kg super(14)CHCl sub(3)) po. Treatment with ABT at 24 h after super(14)CHCl sub(3) dosing decreased the covalent binding of super(14)C to hepatic protein by 35% and reduced the amount of super(14)C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl sub(3) would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl sub(3). These 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 antidotes are administered a number of hours after the initial exposure.