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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 Mice¹

Department of Pharmacology, University of Lund, Sölvegatan 10, S-223 62 Lund [E. B. B.], and Department of Environmental Toxicology, Uppsala University, Box 560, S-751 22 Uppsala [I. B.], Sweden

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 µg/kg) in NMRI mice treated with the cytochrome P4501A-inducing agent ß-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 µM) 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 -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.

¹ This study was supported by the Swedish Council for Forestry and Agricultural Research, the Swedish Environment Protection Board, the Swedish Tobacco Company, the Crafoord Foundation, and the Medical Faculty, University of Lund. Parts of the results were presented at the SOT 1993 Annual Meeting, New Orleans.

² To whom requests for reprints should be addressed.

Received 9/13/93. Accepted 4/ 5/94.

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