Journal Article

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

U.Kristina Walle and Thomas Walle

in Carcinogenesis

Volume 20, issue 11, pages 2153-2157
Published in print November 1999 | ISSN: 0143-3334
Published online November 1999 | e-ISSN: 1460-2180 | DOI:
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

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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 ± 0.7×10–6 cm/s, mean ± SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (Papp 15.1 ± 0.6×10–6 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.

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

Journal Article.  3739 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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