Quantitative studies on the in vitro metabolic activation of dimethylnitrosamine by rat liver postmitochondrial supernatant.
The metabolic activation of dimethylnitrosamine (DMN) to mutagenic and/or cytotoxic intermediates in vitro has been characterized and the relationship between DMN demethylase and ethoxyresorufin-O-deethylase (EROD) or ethylmorphine-N-demethylase (EMND) has been evaluated. A mammalian assay system which uses the postmitochondrial supernatant (S-15 fraction) prepared from a rat liver homogenate as an enzyme source and V79 Chinese hamster cells as targets for chemically induced damage was used. The enzyme pattern of the S-15 fraction was altered by pretreatment of experimental animals in vivo and/or by the use of enzyme inhibitors in vitro. The results of these studies indicate that the concentration of S-15 fraction in the reaction mixture can markedly influence the degree of DMN-induced cytotoxicity when it is metabolized in vitro and that the degree of DMN-induced cytotoxicity and mutagenicity are linearly related. The degree of cytotoxicity and mutagenicity induced in V79 cells by DMN does not correlate with EROD activity (a measure of 3-methylcholanthrene-inducible mixed-function oxidases) nor with EMND activity (a measure of phenobarbital-inducible mixed function oxidases) in the S-15 fraction.
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism*; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D009153:Mutagens; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D007527:Isoenzymes; D009153:Mutagens; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D010089:Oxidoreductases, N-Demethylating; D005037:Ethylmorphine-N-Demethylase; D004128:Dimethylnitrosamine