CHARACTERIZATION OF ACUTE 4,4'-METHYLENE DIANILINE HEPATOTOXICITY IN THE RAT

Methylene dianiline (DDM) is a chemical intermediate in the production of isocyanates and other industrial chemicals, and it is hepatatoxic in humans. The acute hepatotoxicity of orally administered DDM was cha racterized in rats. Rats receiving DDM (25-225 mg/kg, per os) demonstr ated a dose-dependent elevation in serum alanine aminotransferase acti vity, g-glutamyltransferase activity, and serum bilirubin concentratio n. DDM also caused a decrease in bile flow and an elevation in liver w eight. Significant changes in these markers of liver injury occurred b etween 8 and 12 hr after a single, oral administration of DDM. Histolo gically, DDM caused multifocal, necrotizing hepatitis with neutrophil infiltration. Changes in the portal regions consisted of bile ductular necrosis, portal edema, neutrophil infiltration, mild fibrin exudatio n, and segmental necrotizing vasculitis. The role of cytochrome P450 m onooxygenase (MO)-mediated metabolism in DDM hepatotoxicity was evalua ted using the MO inhibitors, aminobenzotriazole and SKF-525A and the M O inducers phenobarbital and beta-naphthoflavone. Aminobenzotriazole p rovided protection from DDM-induced hepatotoxicity, whereas SKF-525A h ad no effect. The effect of phenobarbital pretreatment depended on the dose of DDM administered. At a dose of DDM that produced a maximal he patotoxic response, phenobarbital did not influence hepatotoxicity. Ho wever, phenobarbital pretreatment provided protection against the hepa totoxic effects of a lower dose of DDM. Beta-naphthoflavone pretreatme nt had a more modest effect on DDM induced hepatic insult. These resul ts demonstrate that DDM causes acute hepatotoxicity in the rat that is dose and time dependent. Results using inducers and inhibitors of MO suggest that DDM requires bioactivation to exert toxicity; however, th e relationship between metabolism and toxicity may be complex.