Eb. Brittebo et I. Brandt, 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, Cancer research, 54(11), 1994, pp. 2887-2894
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 microautor
adiographic study showed that there was a highly selective solvent-res
istant binding of radioactive substance in endothelial cells of the pu
lmonary and hepatic portal vascular system and of the vena cava and ty
pe 2 pneumocytes 1 day following i.p. or i.v. injection of [H-3]Trp-P-
1 (100 mu g/kg) in NMRI mice treated with the cytochrome P4501A-induci
ng agent beta-naphthoflavone (BNF). In mice treated with indole-3-carb
inol, a dietary cytochrome P4501A-inducing factor, a similar binding w
as observed in the liver but not in the lung. No binding in endothelia
l cells occurred in vehicle-treated control mice given injections of [
H-3]Trp-P-1. At incubation of tissues with [H-3]Trp-P-1 (0.75 mu M) th
ere was also a selective binding of radioactive substance in endotheli
al cells of the lung and liver and in the vena cava from BNF-treated m
ice but not from vehicle-treated control mice. Ellipticine but not alp
ha-naphthoflavone inhibited the endothelial binding in BNF-treated mic
e exposed to [H-3]Trp-P-1 in vivo or in vitro. No binding of radioacti
ve substance occurred in hepatic central veins or in the aorta of BNF-
treated mice exposed to [H-3]Trp-P-1 in vivo or in vitro. Our data sug
gest an in situ metabolism of [H-3]Trp-P-1 to a reactive species, cata
lyzed by an BNF-inducible P450 form, possibly 1A1, in endothelial cell
s. The results of this study and reported heterocyclic amine-induced t
umors in the rodent vascular system suggest that endothelial cells are
targets for food-derived mutagens.