Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes.
The role of glutathione and cytochrome P-450 in the production of DNA damage by chromium(VI) was examined in chicken embryo hepatocytes by the alkaline elution technique. Cellular levels of glutathione and cytochrome P-450 were altered by treating the hepatocytes with N-acetyl-L-cysteine, buthionine sulfoximine, isopentanol, or beta-naphthoflavone. A dramatic increase in chromium(VI)-induced DNA strand breaks was observed after increasing glutathione levels in the cells. Chromium(VI)-induced DNA strand breaks were even more numerous when the level of cytochrome P-450 was also increased. Upon depletion of glutathione levels and induction of cytochrome P-450 or cytochrome P-448, little or no DNA strand breaks or DNA interstrand cross-links were observed after chromium(VI) treatment. Chromium(VI)-induced DNA-protein cross-links generally decreased after either increases or decreases in cellular levels of glutathione or cytochrome P-450 or P-448. These results suggest that glutathione enhances chromium(VI)-induced DNA damage through metabolic activation of chromium(VI). The possible production of reactive chromium species upon metabolism by glutathione and cytochrome P-450 or P-448 and their involvement in DNA damage is discussed.
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002840:Chromates / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D004261:DNA Replication / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D017670:Sodium Compounds
D002840:Chromates; D017670:Sodium Compounds; C028982:sodium chromate(VI); D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione