Mitochondrial formation of beta-oxopropyl metabolites from bladder carcinogenic omega-carboxyalkylnitrosamines.
Chem Biol Interact
; 90(1): 23-33, 1994 Jan.
Article
em En
| MEDLINE
| ID: mdl-8131217
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinógenos
/
Mitocôndrias
/
Nitrosaminas
Limite:
Animals
Idioma:
En
Revista:
Chem Biol Interact
Ano de publicação:
1994
Tipo de documento:
Article
País de afiliação:
Alemanha