title: Mitochondrial formation of beta-oxopropyl metabolites from bladder carcinogenic omega-carboxyalkylnitrosamines.
abstract: Certain environmentally relevant nitrosamines specifically induce malignant tumors in the urinary bladder in several animal species. For this organotropic effect, formation of omega-carboxylated proximal metabolites has been found to be obligatory. The mechanism of action of these intermediates, however, is not yet clear. We investigated biotransformation of butyl-3-carboxypropylnitrosamine (CAS: 38252-74-3), methyl-3-carboxypropylnitrosamine (CAS: 61445-55-4) and methyl-5-carboxypentylnitrosamine by mitochondrial fractions from rat liver and renal cortex. On incubation with mitochondrial fractions, the respective beta-oxidized metabolites butyl-2-oxopropylnitrosamine (CAS: 51938-15-9) or methyl-2-oxopropylnitrosamine (CAS: 55984-51-51) were formed. This biotransformation was ATP dependent, associated with the presence of mitochondrial marker enzyme (cytochrome c oxidase) in 7000 x g subfractions and was inhibited by octanoic acid. Highest metabolic rates were observed with rat liver fractions. These results demonstrate that omega-carboxylated nitrosamines are substrates for mitochondrial enzymes of fatty acid degradation, most probably following the degradation pathway of medium-chain fatty acids. By this reaction, water-soluble carboxylated nitrosamines of low genotoxic potential are converted into rather lipophilic 2-oxopropyl metabolites with high genotoxic and carcinogenic potency. In contrast to carboxylated metabolites, 2-oxopropyl derivatives are good substrates for cytochrome P-450 dependent mono-oxygenases. Therefore, mitochondrial beta-oxidation appears to be an important step in metabolic activation of nitrosamines tumorigenic in the urinary bladder.
authors.affiliation: Department of Chemistry, Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Janzowski
authors.forename: R
authors.initials: R
authors.lastname: Landsiedel
authors.forename: P
authors.initials: P
authors.lastname: Gölzer
authors.forename: G
authors.initials: G
authors.lastname: Eisenbrand
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism* / Q000633:toxicity; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C006853:butyl(3-carboxypropyl)nitrosamine; C006861:butyl(2-oxopropyl)nitrosamine; C044779:4-(N-nitroso-N-methylamino)butyric acid