Potentiation of the hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone, and isopropanol.
Previous studies indicate that pretreatment with acetone or isopropanol, fasting, and streptozotocin-induced diabetes enhance hepatic microsomal nitroso-dimethylamine (NDMA) demethylase in rats. This study demonstrates that these same treatments also potentiate the hepatotoxicity of NDMA as indicated by plasma glutamic pyruvate transaminase (GPT) levels and histologic data. Pretreatment with acetone or isopropanol (2.5 ml/kg) and 2 days of fasting caused a 2-fold potentiation of NDMA-induced plasma GPT elevation, whereas streptozotocin-induced diabetes caused a 4.6-fold potentiation. The centrilobular necrosis produced by NDMA was more severe after pretreatment with the inducers. NDMA treatment also decreased hepatic microsomal demethylase activity. These results lend support to the concept that a NDMA demethylase is responsible for the activation of NDMA in vivo to a toxic intermediate, and induction of this enzyme activity potentiates NDMA hepatotoxicity.
D000433:1-Propanol / Q000633:toxicity*; D000096:Acetone / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004128:Dimethylnitrosamine / Q000378:metabolism / Q000633:toxicity*; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005215:Fasting / Q000009:adverse effects*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D000096:Acetone; D003577:Cytochrome P-450 Enzyme System; D000433:1-Propanol; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine