Document Detail


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.
MedLine Citation:
PMID:  10545419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 [(3)H]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 microM. Still, the basolateral to apical efflux [apparent permeability coefficient (P(app)) 54.2 +/- 0.7x10(-6) cm/s, mean +/- SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (P(app) 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.
Authors:
U K Walle; T Walle
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Carcinogenesis     Volume:  20     ISSN:  0143-3334     ISO Abbreviation:  Carcinogenesis     Publication Date:  1999 Nov 
Date Detail:
Created Date:  2000-01-03     Completed Date:  2000-01-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  2153-7     Citation Subset:  IM    
Affiliation:
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
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MeSH Terms
Descriptor/Qualifier:
Biological Transport
Caco-2 Cells
Food*
Humans
Imidazoles / pharmacokinetics*
Intestines / cytology,  metabolism*
Mutagens / pharmacokinetics*
P-Glycoprotein / antagonists & inhibitors
Verapamil / pharmacology
Grant Support
ID/Acronym/Agency:
CA69138/CA/NCI NIH HHS; GM55561/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Imidazoles; 0/Mutagens; 0/P-Glycoprotein; 105650-23-5/2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; 52-53-9/Verapamil

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