Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice.
The effects of methoxsalen, a potent inhibitor of cytochrome P-450, on the hepatotoxicity and nephrotoxicity of chloroform have been determined in mice. Hepatic and renal monooxygenase activities and the in vitro covalent binding of chloroform metabolites to hepatic and renal microsomal proteins were decreased by 20-70% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol.kg-1ip) alone. Administration of methoxsalen (250 mumol.kg-1ip), 30 min before [14C]chloroform (1 ml.kg-1ip), did not modify blood levels of [14C]chloroform (and metabolites) but decreased the in vivo covalent binding of [14C]chloroform metabolites to hepatic and renal proteins 4 hr after the administration of [14C]chloroform. This pretreatment markedly decreased serum glutamic pyruvic transaminase activity, blood urea nitrogen, glucosuria, liver and kidney lesions, and mortality 24 hr after the administration of chloroform (0.125-1.5 ml.kg-1ip). Other cytochrome P-450 inhibitors (SKF 525-A or piperonyl butoxide), given at the same molar dose (250 mumol.kg-1ip), exerted no protective effect. Pretreatment with methoxsalen appears to decrease the metabolic activation of chloroform and essentially prevents its hepatotoxicity and nephrotoxicity in mice. Methoxsalen may have use as a tool to determine the role of metabolic activation by cytochrome P-450 in the hepatotoxicity and nephrotoxicity of drugs and chemicals.
D015660:7-Alkoxycoumarin O-Dealkylase; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002725:Chloroform / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism
D011506:Proteins; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D008730:Methoxsalen