Unaltered expression of multidrug resistance transporters in polycyclic aromatic hydrocarbon-resistant rat liver cells.
Rat liver epithelial cells resistant to the chemical carcinogen 3MC, termed F258/3MC cells and generated by long-term exposure of parental F258 cells to the PAH, were characterized, especially with respect to expression of multidrug resistance transporters such as P-glycoprotein, MRP1 and MRP2. F258/3MC cells were found to be cross-resistant to other PAHs such as BP and dimethylbenz(a)anthracene but remained sensitive to known substrates of multidrug resistance efflux pumps such as doxorubicin and vincristine. They did not display either decreased cellular PAH accumulation or increased PAH efflux. In addition, P-glycoprotein and MRP2 mRNA levels were not, or only barely detected, in F258/3MC cells and in their parental counterparts whereas these PAH-resistant and sensitive cells showed closed levels of MRP1 mRNAs and activity. Moreover, P-gp- and MRP1-overexpressing cells were shown to display similar accumulation and efflux of BP than those found in P-gp- and MRP1-negative control cells. These data therefore suggest that multidrug resistance transporters do not contribute to PAH resistance in PAH-selected liver cells.
Payen
L
L
INSERM U456, Detoxication et Reparation Tissulaire, Faculté de Pharmacie, 2 Avenue du Pr L. Bernard, 35043 Rennes Cedex, France.
Courtois
A
A
Langouët
S
S
Guillouzo
A
A
Fardel
O
O
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008748:Methylcholanthrene / Q000633:toxicity; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology
D015127:9,10-Dimethyl-1,2-benzanthracene; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001580:Benzopyrenes; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D018736:DNA Adducts; D004317:Doxorubicin; D026901:Membrane Transport Proteins; D008748:Methylcholanthrene; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D014750:Vincristine; C421109:multidrug resistance-associated protein 1