title: Metabolic activation of the food mutagen 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole (Trp-P-1) in endothelial cells of cytochrome P-450-induced mice.
abstract: 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a carcinogen which is metabolically activated by cytochrome P4501A. This microautoradiographic study showed that there was a highly selective solvent-resistant binding of radioactive substance in endothelial cells of the pulmonary and hepatic portal vascular system and of the vena cava and type 2 pneumocytes 1 day following i.p. or i.v. injection of [3H]Trp-P-1 (100 micrograms/kg) in NMRI mice treated with the cytochrome P4501A-inducing agent beta-naphthoflavone (BNF). In mice treated with indole-3-carbinol, a dietary cytochrome P4501A-inducing factor, a similar binding was observed in the liver but not in the lung. No binding in endothelial cells occurred in vehicle-treated control mice given injections of [3H]Trp-P-1. At incubation of tissues with [3H]Trp-P-1 (0.75 microM) there was also a selective binding of radioactive substance in endothelial cells of the lung and liver and in the vena cava from BNF-treated mice but not from vehicle-treated control mice. Ellipticine but not alpha-naphthoflavone inhibited the endothelial binding in BNF-treated mice exposed to [3H]Trp-P-1 in vivo or in vitro. No binding of radioactive substance occurred in hepatic central veins or in the aorta of BNF-treated mice exposed to [3H]Trp-P-1 in vivo or in vitro. Our data suggest an in situ metabolism of [3H]Trp-P-1 to a reactive species, catalyzed by an BNF-inducible P450 form, possibly 1A1, in endothelial cells. The results of this study and reported heterocyclic amine-induced tumors in the rodent vascular system suggest that endothelial cells are targets for food-derived mutagens.
authors.affiliation: Department of Pharmacology, University of Lund, Sweden.
authors.forename: E B
authors.initials: EB
authors.lastname: Brittebo
authors.forename: I
authors.initials: I
authors.lastname: Brandt
mesh_terms: D000818:Animals; D001345:Autoradiography; D001571:Benzoflavones; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D019324:beta-Naphthoflavone
chemical_list: D001571:Benzoflavones; D002243:Carbolines; D009153:Mutagens; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole