Metabolism of 1- and 2-naphthylamine in isolated rat hepatocytes.
The liver probably plays a major role in the metabolic activation of the bladder carcinogen 2-naphthylamine (2-NA) and in the inactivation of the non-carcinogenic isomer 1-naphthylamine (1-NA). However, metabolic profiles of these compounds (including primary metabolites and directly determined conjugates) in hepatocytes are not available. Therefore metabolism of 1- and 2-NA was compared in freshly isolated hepatocytes from 3-methylcholanthrene (MC)-treated and untreated rats. At 10 microM, 2-NA was found to be mainly N-acetylated (66% of total metabolites after 1 h incubation) and N-glucuronidated (19%). Minor pathways led to C-oxidation (7%) and N-oxidation (3%; 2% present as the N-glucuronide). In hepatocytes from MC-treated rats total metabolism was slightly affected (1.5-fold increase). However, C- and N-oxidation were markedly increased (63 and 18% respectively), while N-acetylation and N-glucuronidation were diminished (5 and 2% respectively). Similar experiments were carried out with 1-NA. Its N-glucuronide was the predominant metabolite (68%) followed by the N-acetylated compound (15%) while C-oxidation was low and N-oxidized metabolites could not be detected, even after induction. The results demonstrate that MC treatment markedly shifted 2-NA metabolism from N-acetylation and N-glucuronidation to N- and C-oxidation. In the case of 1-NA metabolism extensive N-glucuronidation together with the lack of N-oxidation may prevent carcinogenesis.
Orzechowski
A
A
Institute of Toxicology, University of Tübingen, Germany.
Schrenk
D
D
Bock
K W
KW
D015057:1-Naphthylamine / Q000378:metabolism*; D015081:2-Naphthylamine / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000008:administration & dosage; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D008748:Methylcholanthrene; D015057:1-Naphthylamine; D015081:2-Naphthylamine