Metabolism and cytotoxicity of aflatoxin B1 in cultured rat hepatocytes and nonparenchymal cells: implications for tumorigenesis.
Liver cells, isolated from male Sprague-Dawley rats and established in primary culture, were treated with a dose of 180 pmol aflatoxin B1 (AFB1) for 2 hr. Reticuloendothelial nonparenchymal cells (NPC) metabolized a total of 28% of the AFB1. In contrast, parenchymal epithelial cells or hepatocytes (HC) were highly efficient in conjugating AFB1 to water-soluble products (50-70% of the dose) but also bound a large proportion (27%) of the toxin to cellular macromolecules. In comparison to NPC, HC bound 90-fold more AFB1 per cell. Cytotoxicity in primary cultures was evaluated by changes in membrane integrity (lactate dehydrogenase release), inhibition of glutathione-S-transferase activity and cell monolayer morphology over a range of AFB1 doses. No response was detected in NPC, whereas HC exhibited dose-related cytotoxic responses to AFB1. In rat liver both cell types form AFB1-DNA adducts in a dose-dependent fashion and yet only epithelial cell carcinomas have been observed in whole animal studies. The possibility that cell-specific AFB1 cytotoxicity produces a promotional stimulus for hepatocellular carcinoma is discussed.
Jennings
G S
GS
Institute of Toxicology, University of Mainz, Germany.
Heck
R
R
Oesch
F
F
Steinberg
P
P
D016604:Aflatoxin B1 / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced; D002452:Cell Count / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004356:Drug Storage; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water
D018736:DNA Adducts; D014867:Water; D004247:DNA; D016604:Aflatoxin B1; D007770:L-Lactate Dehydrogenase; D005982:Glutathione Transferase