Evidence for the metabolism of N-nitrosodimethylamine and carbon tetrachloride by a common isozyme of cytochrome P-450.
Carbon tetrachloride administration to rats produced a selective loss of hepatic cytochrome P-450-dependent catalytic activities. Of the cytochrome P-450-dependent catalytic activities tested, the metabolism of carbon tetrachloride to phosgene and the low Km N-nitrosodimethylamine demethylase were the most sensitive to destruction by carbon tetrachloride. A 50% or greater loss in these catalytic activities was observed 3 hr after giving 10 microliters carbon tetrachloride/kg. Related catalytic activities, such as the microsomal metabolism of carbon tetrachloride to chloroform and the high Km N-nitrosodimethylamine demethylase, were diminished less than 20% 3 hr after giving 10 microliters carbon tetrachloride/kg. To investigate further the relationship between the metabolism of N-nitrosodimethylamine and carbon tetrachloride, the effect of pyrazole, a known inducer of the low Km N-nitrosodimethylamine demethylase, on carbon tetrachloride metabolism was studied. Pyrazole treatment produced a 5.6-fold increase in the microsomal metabolism of carbon tetrachloride to phosgene and a 1.9-fold increase in the conversion of carbon tetrachloride to chloroform. The similarities between both the loss and the induction of the low Km N-nitrosodimethylamine demethylase and the metabolism of carbon tetrachloride to phosgene suggest that these catalytic activities represent a common isozyme of cytochrome P-450. Analysis of cytochromes P-450 by HPLC provided evidence for an isozyme of cytochrome P-450 inducible by pyrazole and destroyed by carbon tetrachloride.
English
J C
JC
Anders
M W
MW
D000818:Animals; D002251:Carbon Tetrachloride / Q000378:metabolism* / Q000494:pharmacology; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine