MITOCHONDRIAL FORMATION OF BETA-OXOPROPYL METABOLITES FROM BLADDER CARCINOGENIC OMEGA-CARBOXYALKYLNITROSAMINES

Certain environmentally relevant nitrosamines specifically induce mali gnant tumors in the urinary bladder in several animal species. For thi s organotropic effect, formation of omega-carboxylated proximal metabo lites has been found to be obligatory. The mechanism of action of thes e intermediates, however, is not yet clear. We investigated biotransfo rmation of butyl-3-carboxypropylnitrosamine (CAS: 38252-74-3), methyl- 3-carboxypropylnitrosamine (CAS: 61445-55-4) and methyl-5-carboxypenty lnitrosamine by mitochondrial fractions from rat liver and renal corte x. On incubation with mitochondrial fractions, the respective beta-oxi dized metabolites butyl-2-oxopropylnitrosamine (CAS: 51938-15-9) or me thyl-2-oxopropylnitrosamine (CAS: 55984-51-51) were formed. This biotr ansformation was ATP dependent, associated with the presence of mitoch ondrial marker enzyme (cytochrome c oxidase) in 7000 x g subfractions and was inhibited by octanoic acid. Highest metabolic rates were obser ved with rat liver fractions. These results demonstrate that omega-car boxylated nitrosamines are substrates for mitochondrial enzymes of fat ty acid degradation, most probably following the degradation pathway o f medium-chain fatty acids. By this reaction, water-soluble carboxylat ed nitrosamines of low genotoxic potential are converted into rather l ipophilic 2-oxopropyl metabolites with high genotoxic and carcinogenic potency. In contrast to carboxylated metabolites, 2-oxopropyl derivat ives are good substrates for cytochrome P-450 dependent monooxygenases . Therefore, mitochondrial beta-oxidation appears to be an important s tep in metabolic activation of nitrosamines tumorigenic in the urinary bladder.