Characterization of chromium effects on a rat liver epithelial cell line and their relevance to in vitro transformation.
Chronic exposure to low concentrations or brief exposures to high concentrations of hexavalent chromium (K2CrO4) transformed a rat liver epithelial cell line as assessed by anchorage-independent growth. A clone of the transformed cells produced tumors in syngeneic animals, all of which were determined to be high grade carcinomas. The effects of various doses of chromium on cytotoxicity and cell cycle were established and related to ultimate numbers of transformants in the population. Prior to the onset of cytotoxicity, linear rates of uptake were observed at different external concentrations of chromium and the total intracellular level increased with increasing concentration. This may be due to competition for transport. A plateau in level of chromium accumulation after prolonged exposure to a low concentration (10 microM) of chromium observed with the eventual return to normal growth provided evidence for the induction of a protective mechanism. In addition, cells surviving prolonged treatment with low concentrations of chromium became resistant to the cytotoxic effects of high concentrations of the metal, further suggesting that the cells become adapted to the presence of chromium. An increase in the amount of protein associated with extracted nucleic acids was detected at the optimal transforming dose and this did not correlate with cytotoxic effects. The effectiveness of chromium in transforming the adult rat liver epithelial cell line may depend on the intracellular level of accumulation, the rate of chromium uptake, and the ability of the cell to activate a protective mechanism. The initiation of stable nucleic acid-protein complexes observed under the optimal conditions for transformation may be associated with an inability of the cell to activate a protective mechanism rapidly enough to prevent effects on the nucleus at a high concentration (1 mM) of chromium.
Briggs
J A
JA
Department of Biochemistry, Vanderbilt University Cancer Center, Nashville, Tennessee.
Briggs
R C
RC
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002857:Chromium / Q000493:pharmacokinetics / Q000633:toxicity*; D004247:DNA / Q000032:analysis; D004848:Epithelium / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D008099:Liver / Q000187:drug effects*; D009368:Neoplasm Transplantation; D011506:Proteins / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344
D011506:Proteins; D002857:Chromium; D004247:DNA; D005978:Glutathione