Metabolism-dependent binding of the heterocyclic amine Trp-P-1 in endothelial cells of choroid plexus and in large cerebral veins of cytochrome P450-induced mice.

Trp-P-1 (3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole) is known to be metabolized by cytochrome P4501A (P4501A) to reactive intermediates which may bind irreversibly to tissue macromolecules. The irreversible binding of [3H]Trp-P-1 in the brain of NMRI-mice was studied by microautoradiography. There was a selective irreversible binding of radioactivity in endothelial cells following an i.v. or i.p. injection of [3H]Trp-P-1 (100 micrograms/kg or 1.5 mg/kg) in mice treated with the P4501A-inducing agent beta-naphthoflavone (BNF). The binding of radioactivity was highest in capillary loops of the choroid plexus, less marked in large cerebral veins and in arachnoidal veins whereas no binding was observed in cerebral capillaries, arteries, neurons or in other brain cells. In endothelial cells of vehicle-treated control mice injected with [3H]Trp-P-1 no binding of radioactivity was observed. At incubation of brain slices with [3H]Trp-P-1, there was a marked irreversible binding of radioactivity in endothelial cells in the choroid plexus of BNF-treated mice but not in vehicle-treated control mice. The P4501A inhibitor ellipticine abolished the BNF-induced endothelial binding of [3H]Trp-P-1-derived radioactivity in vivo and in vitro. The marked binding of Trp-P-1-derived radioactivity in endothelial cells of the choroid plexus of BNF-treated mice demonstrate that a BNF-responsive enzyme activity, possibly P4501A, may be induced at this site and suggests that a P450-dependent enzyme activity be part of the blood-cerebrospinal fluid barrier regulating the transendothelial passage of compounds.