title: Mechanism of action of the urinary bladder carcinogen N-nitrosobutyl-3-carboxypropylamine.
abstract: The carcinogenic action of N-nitrosodibutylamine in the urinary bladder is related to omega-oxidation of a butyl chain. N-Nitrosobutyl-4-hydroxybutylamine and its proximate metabolite N-nitrosobutyl-3-carboxypropylamine (NBCPA) selectively induce urinary bladder tumours in different animal species. The mechanism by which NBCPA exert its carcinogenic action is not known. We found a small but significant dealkylation of NBCPA with microsomes from rat liver or pig urinary bladder, which could be inhibited by SKF 525A. NBCPA was not mutagenic to Salmonella typhimurium (with or without external metabolizing systems from rat liver or pig urinary bladder) and did not induce DNA strand breaks in tumour cell lines (with or without external activation) or primary cells (rat hepatocytes, pig urinary bladder epithelia). Significant induction of sister chromatid exchange and micronuclei, however, was observed in human tumour cells. N-Nitrosoureas that generate the same electrophiles as NBCPA after alpha- or via beta-oxidation (N-butyl-N-nitrosourea, N-3-carboxypropyl-N-nitrosourea and N-2-oxopropyl-N-nitrosourea) induced single-strand breaks in Namalva cells, the oxopropyl compound being more potent than the butyl or carboxypropyl compounds. Our data suggest that NBCPA is activated via alpha-oxidation in the urinary bladder, even though the activation rate in vitro is so low that a positive response is not detectable by classical short-term tests. Provided that beta-oxidation to a highly genotoxic agent proceeds at an adequate rate, it might also be a relevant activation pathway.
authors.affiliation: Department of Food Chemistry, University of Kaiserslautern, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Janzowski
authors.forename: D
authors.initials: D
authors.lastname: Jacob
authors.forename: I
authors.initials: I
authors.lastname: Henn
authors.forename: H
authors.initials: H
authors.lastname: Zankl
authors.forename: B L
authors.initials: BL
authors.lastname: Pool-Zobel
authors.forename: M
authors.initials: M
authors.lastname: Wiessler
authors.forename: G
authors.initials: G
authors.lastname: Eisenbrand
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D004249:DNA Damage; D008861:Microsomes / Q000378:metabolism; D009602:Nitrosamines / Q000633:toxicity*; D009607:Nitrosourea Compounds / Q000633:toxicity; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D009607:Nitrosourea Compounds; C006853:butyl(3-carboxypropyl)nitrosamine