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Carcinogenesis, Vol. 20, No. 11, 2153-2157, November 1999
© 1999 Oxford University Press

Carcinogenesis

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

U.Kristina Walle and Thomas Walle1

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, PO Box 250505, Charleston, SC 29425, USA

Cooked-food mutagens formed when frying meat have been suggested to contribute to the etiology of colon, breast and prostate cancer. The most prevalent of these mutagens is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which after absorption is bioactivated by both phase I and phase II enzymes. Although available data suggest absorption of PhIP in humans, the extent and mechanism of absorption are unknown. In the present study we examined the transport of [3H]PhIP through the human Caco-2 intestinal epithelial 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 concentration of 5 µM. Still, the basolateral to apical efflux [apparent permeability coefficient (Papp) 54.2 ± 0.7x10–6 cm/s, mean ± SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (Papp 15.1 ± 0.6x10–6 cm/s, n = 21, P < 0.0001). Equilibrium exchange experiments demonstrated the efflux to be a true active process. Preincubations with verapamil, an inhibitor of P-glycoprotein-mediated transport, or MK-571, an inhibitor of multidrug resistance-associated protein-mediated transport, stimulated influx and reduced efflux of PhIP, suggesting that PhIP is a substrate for both of these transporters. These findings should be considered when determining exposure to the cooked food mutagens.

Abbreviations: HBSS, Hanks' balanced salt solution; MRP, multidrug resistance-associated protein; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

1 To whom correspondence should be addressed Email: wallet{at}musc.edu


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