Acute cytotoxicity of the chemical carcinogen 2-acetylaminofluorene in cultured rat liver epithelial cells.
Acute cytotoxic effects of 2-acetylaminofluorene (AAF), a powerful chemical carcinogen, were studied in cultured rat liver epithelial F258 cells. Acute treatment of these cells by AAF resulted in inhibition of cell proliferation, through an arrest in G0/G1 phase of the cell cycle, and a loss of cell viability. By contrast, AAF failed to trigger apoptosis as demonstrated by flow cytometric analysis of hypoploid sub-G1 cells. Cytochrome P4501A1 (CYP1A1), a drug metabolizing enzyme thought to play a major role in biotransformation of AAF, was induced in AAF-treated F258 cells as assessed by Northern blotting. AAF cytotoxic effects were however not blocked by the CYP1A1 inhibitor alpha-naphtoflavone, thus suggesting that they did not require CYP1A1 activity. They were also not prevented by the antioxidant N-acetylcysteine, making unlikely a major contribution of AAF-related reactive oxygen species. These data therefore indicate that AAF can exert acute cellular toxicity, including inhibition of cell growth and cell death, in rat liver epithelial cells without triggering an apoptotic process. Such an acute toxicity may contribute to the well-known promoting effects of AAF.
Sparfel
Lydie
L
INSERM U456, Faculté de Pharmacie, 2 Avenue du Pr L. Bernard, 35043, Rennes, France.
Loewert
Maud
M
Huc
Laurence
L
Payen
Léa
L
Guillouzo
André
A
Lagadic-Gossmann
Dominique
D
Fardel
Olivier
O
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001571:Benzoflavones / Q000494:pharmacology; D015152:Blotting, Northern; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D001571:Benzoflavones; D002273:Carcinogens; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C011512:alpha-naphthoflavone; D015073:2-Acetylaminofluorene; D019363:Cytochrome P-450 CYP1A1; D000111:Acetylcysteine