Oxidation of N-butyl-N-(3-formylpropyl)nitrosamine to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver and inhibition by disulfiram.
The metabolism of N-butyl-N-(3-formylpropyl)nitrosamine, a presumptive intermediate metabolite of the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine, by rat liver has been examined. N-Butyl-N-(3-formylpropyl)nitrosamine was metabolized by an NADH-dependent reduction to N-butyl-N-(4-hydroxybutyl)nitrosamine and by an NAD+-dependent oxidation to N-butyl-N-(3-carboxypropyl)nitrosamine. The reduction of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited by pyrazole. The oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was studied further. The rate of oxidation in total rat liver was 3 mumol/min/g liver or 21 nmol/min/mg protein and was similar to that found for the oxidation of propionaldehyde, a model substrate for isozymes of rat liver aldehyde dehydrogenase. The rate of oxidation of N-butyl-N-(3-formylpropyl)nitrosamine by isozymes in rat liver cytosol was 2-2.5 times that found for propionaldehyde. The apparent Km for the NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was 20-30 microM, which is considerably lower than values reported for known substrates of aldehyde dehydrogenase. The NAD+-dependent oxidation of N-butyl-N-(3-formylpropyl)nitrosamine was inhibited 40-50% by 50 microM disulfiram, 60-70% by 100 microM disulfiram, and 50% by 0.4 mM sodium arsenite. These studies show that N-butyl-N-(3-formylpropyl)nitrosamine is very rapidly oxidized to N-butyl-N-(3-carboxypropyl)nitrosamine in rat liver by aldehyde dehydrogenase and the results may help to explain why the 3-formylpropyl intermediate has not been directly identified as a metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine in urine or in isolated hepatocytes.
Irving
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CC
Research Service, Veterans Administration Medical Center, Memphis, TN.
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D009602:Nitrosamines; D009243:NAD; C006853:butyl(3-carboxypropyl)nitrosamine; C057605:N-butyl-N-(3-formylpropyl)nitrosamine; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram