Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps

Cooked-food mutagens formed when frying meat have been suggested to contrib ute to the etiology of colon, breast and prostate cancer. The most prevalen t of these mutagens is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhI P), which after absorption is bioactivated by both phase I and phase II enz ymes. Although available data suggest absorption of PhIP in humans, the ext ent and mechanism of absorption are unknown. In the present study we examin ed the transport of [H-3]PhIP through the human Caco-2 intestinal epithelia l cell monolayer, a well-accepted model of human intestinal absorption. The influx, or absorption, was extensive and linear for 2 h and up to a PhIP c oncentration of 5 mu M. Still, the basolateral to apical efflux [apparent p ermeability coefficient (P-app) 54.2 +/- 0.7 x 10(-6) cm/s, mean +/- SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (P-app 1 5.1 +/- 0.6 x 10(-6) cm/s, n = 21, P < 0.0001). Equilibrium exchange experi ments demonstrated the efflux to be a true active process. Preincubations w ith verapamil, an inhibitor of P-glycoprotein-mediated transport, or MK-571 , an inhibitor of multidrug resistance-associated protein-mediated transpor t, stimulated influx and reduced efflux of PhIP, suggesting that PhIP is a substrate for both of these transporters. These findings should be consider ed when determining exposure to the cooked food mutagens.