Metabolic activation of the food mutagen Trp-P-1 in endothelial cells of heart and kidney in cytochrome P450-induced mice.
Trp-P-1 (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole) is a carcinogen metabolized by hepatic cytochrome P4501A (P4501A). This study showed that there was a highly selective solvent-resistant binding of radioactive substance in endothelial cells of heart and kidney 1 day following injection of [3H]-Trp-P-1 (0.1 or 1.5 mg/kg) in NMRI mice treated with the P450-inducing agent beta-naphthoflavone (BNF). In the heart, the binding was highest in capillaries and coronary vessels. In the kidney, the binding was highest in afferent and efferent arterioles and glomerular and peritubular capillaries. A corresponding localization of radioactivity did not occur in corn oil-treated mice injected with [3H]-Trp-P-1. On incubation of heart and kidney slices with [3H]-Trp-P-1, there was a binding of radioactivity in endothelial cells of BNF-treated mice, but not in corn oil-treated mice. The P4501A inhibitor ellipticine abolished the BNF-induced endothelial binding of [3H]-Trp-P-1 in vivo and in vitro, whereas the effects of alpha-naphthoflavone were inconsistent. The results indicate an in situ metabolism of [3H]-Trp-P-1 to a reactive species, catalysed by a BNF-inducible enzyme, possibly P4501A1, in endothelial cells in the heart and kidney. Since related heterocyclic amines induce tumors and other lesions in the rodent vascular system, the results raise the possibility that Trp-P-1 and other food mutagens may play a role in cardiovascular disease.
Brittebo
E B
EB
Department of Pharmacology, University of Lund, Sweden.
D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004727:Endothelium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens; D009206:Myocardium / Q000378:metabolism*
D002243:Carbolines; D065607:Cytochrome P-450 Enzyme Inhibitors; D009153:Mutagens; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole