The drug methoxsalen, a suicide substrate for cytochrome P-450, decreases the metabolic activation, and prevents the hepatotoxicity, of carbon tetrachloride in mice

Abstract

Methoxsalen, a potent suicide inhibitor of cytochrome P-450 that can be used in humans, might be of value for the prevention of hepatitis in subjects with carbon tetrachloride poisoning. As a preliminary step, we have determined its effects on the hepatotoxicity of carbon tetrachloride in mice. Several monooxygenase activities, the in vitro covalent bincling of carbon tetrachloride metabolites to microsomal proteins, and in vitro microsomal lipid peroxidation initiated by carbon tetrachloride metabolites were decreased by 60–90% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 μmol · kg −1) ; microsomal lipid peroxidation mediated by endogenous iron and NADPH was not modified. Administration of methoxsalen (250 μmol · kg −1) 30min before carbon tetrachloride (0.1 ml · kg −1) decreased both the in vivo formation of conjugated dienes in microsomal lipids and the in vivo covalent bincling of carbon tetrachloride metabolites to lipids and proteins. This pretreatment completely prevented the hepatotoxicity of carbon tetrachloride. Other cytochrome P-450 inhibitors (cimeticline, SKF 525-A or piperonyl butoxide) given at this low molar dose (250 μmol · kg −1) exerted no protective effect. Methoxsalen (500 μmol · kg −1) was also effective, but only partially, when given 30 min after carbon tetrachloride (0.025 ml · kg −1). We conclude that pretreatment with methoxsalen decreases the metabolic activation of carbon tetrachloride, and completely prevents its hepatotoxicity in mice. Post-treatment with methoxsalen must be given early and is only partially effective in mice.