The genotoxic effects of arachidonic acid in V79 cells are mediated by peroxidation products.
Chinese hamster lung fibroblasts (V79 cells) were exposed to 2, 20, 160, and 200 microM arachidonic acid (AA). At 20 microM, a stimulatory effect on cell growth was observed, while at 200 microM, an inhibitory effect was found. AA at 160 and 200 microM induced a 10- to 12-fold increase of 6-thioguanine-resistant mutants in V79 cells, whereas increased alkaline labile sites on DNA were consistently produced only with 200 microM treatment doses. The induction of alkaline labile lesions was partially inhibited in the presence of an antioxidant NDGA. [3H]AA metabolism in cells was examined by HPLC analysis following reductive transmethylation of the cell lipid extracts. Two fractions corresponding to [3H]AA-derived peroxidation products were identified by HPLC-radiochromatography and analyzed by mass spectrometry. Quantitative evaluation of the radioactivity associated with these peaks revealed an increase in [3H]AA peroxidation products when cells were exposed to increasing amounts of AA. The AA-dependent stimulation of lipid peroxidation product formation was partially inhibited when cells were treated in the presence of NDGA. The results provide evidence that substantially enlarged AA pools in cells may induce genotoxic effects mediated through increased endogenous lipid peroxidation products.
Zhang
J R
JR
Institute of Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.
Sevanian
A
A
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation; D008168:Lung / Q000166:cytology; D009637:Masoprocol / Q000494:pharmacology; D009154:Mutation; D013866:Thioguanine / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D014810:Vitamin E; D016718:Arachidonic Acid; D009637:Masoprocol; D013866:Thioguanine