PRETREATMENT OR POSTTREATMENT WITH METHOXSALEN PREVENTS THE HEPATOTOXICITY OF ACETAMINOPHEN IN MICE

We have reported previously that methoxsalen is a suicide substrate for cytochrome P-450. We now report its effects on the metabolism and toxicity of acetaminophen in mice. Intragastric administration of methoxsalen (125 mumol X kg-1), 30 min before that of acetaminophen (600 mg X kg-1 i.p.), decreased the formation of the mercapturate and cysteine conjugates of acetaminophen, the depletion of glutathione and the in vivo covalent binding of an acetaminophen metabolite to hepatic proteins and prevented the increase in serum glutamic-pyruvic transaminase activity, the appearance of liver lesions and mortality. Methoxsalen (250 mumol X kg-1) also afforded complete protection when given intragastrically 2 hr after acetaminophen (600 mg X kg-1 i.p.). At that time, methoxsalen still decreased in vivo covalent binding measured per whole liver, and permitted a faster recovery of hepatic glutathione. Methoxsalen (180 mumol X kg-1) and N-acetylcysteine (919 mumol X kg-1) exerted additive protective effects when given concomitantly 2 hr after acetaminophen. We conclude that administration of methoxsalen decreases the metabolic activation and the hepatotoxicity of acetaminophen in mice.