Role of the multidrug resistance protein 1 gene in the carcinogenicity of aflatoxin B1: investigations using mrp1-null mice.
The multidrug resistance protein 1 (MRP1) protects cells from xenobiotics by extruding from the intracellular compartment glutathione (GSH)-S-conjugates, glucuronyl conjugates and sulfate conjugates and by the co-export of xenobiotic(s) and GSH. An ATP-dependent transport of aflatoxin B1 (AFB1) and its GSH conjugates by MRP1 has been previously demonstrated in vitro. In the present study, we have sought to investigate the in vivo role of MRP1 in AFB1 carcinogenicity, by comparing the incidence of tumors occurring in mrp1 (+/+) and mrp1 (-/-) mice 12 months after an 8 weeks exposure to AFB1. The carcinogen induced a similar number of lung and liver tumors in both strains. Most lung tumors were of the solid type and showed a moderate degree of differentiation in both mrp1 (+/+) and mrp1 (-/-) mice. These data provide direct evidence that in vivo MRP1 does not protect from AFB1 carcinogenicity. Due to the redundancy of transmembrane export pumps, other pump(s) may effectively vicariate for MRP1-mediated transport of AFB1 and its glutathione conjugates.
Lorico
Aurelio
A
Department of Tumor Biology, The Norwegian Radium Hospital, University of Oslo, Montebello, N-0310, Oslo, Norway. aureliol@labmed.uio.no
Nesland
Jahn
J
Emilsen
Elisabeth
E
Fodstad
Oystein
O
Rappa
Germana
G
D016604:Aflatoxin B1 / Q000009:adverse effects* / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics*; D019450:Genes, MDR; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein
D016604:Aflatoxin B1; D002273:Carcinogens; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1