In vitro toxicity of 7H-dibenzo[c,g]carbazole in human liver cell lines.
7H-Dibenzo[c,g]carbazole (DBC) is a model N-heterocyclic aromatic compound (NHA) which is both a hepatotoxin and hepatocarcinogen in rodents. The focus of this investigation was to determine whether human liver cell lines display differential sensitivities to DBC-induced toxicity. Treatment of cell lines with increasing DBC concentrations produced apoptosis only in HepG2 cells. Although DBC inhibited the clonogenic growth of all cell lines at high concentrations, only the survival of HepG2 cells was reduced at lower concentrations. DBC inhibited DNA synthesis in two (HepG2, HLF) of the three cell lines at lower concentrations and was effective only at a high concentration in Mahlavu cells. Differences in DBC uptake were not observed in any of the cell lines, suggesting that bioavailability was not a limiting factor. DBC-DNA adducts were not detected in HLF or Mahlavu cells at either low or high concentrations of DBC. Consistent with the DNA adduct data, RP-HPLC analysis indicated that DBC was metabolized to a lesser degree in the HLF and Mahlavu cells. These results suggest that human liver cell lines differ markedly in the ability to metabolize DBC to toxic species and that DBC-induced apoptosis is only observed in cells that produce detectable metabolites and DBC-DNA adducts.
O'Brien
T
T
Department of Environmental Health, University of Cincinnati Medical Center, ML0056 Cincinnati OH 45267-0056, USA.
Schneider
J
J
Warshawsky
D
D
Mitchell
K
K
D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000096:biosynthesis; D018736:DNA Adducts / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D002273:Carcinogens; D018736:DNA Adducts; D004273:DNA, Neoplasm; D019384:Nucleic Acid Synthesis Inhibitors; D004247:DNA; C013478:7H-dibenzo(c,g)carbazole