Induction of cytotoxicity and mutagenesis is facilitated by fatty acid hydroperoxidase activity in Chinese hamster lung fibroblasts (V79 cells).
The metabolic activation of benzo[a]pyrene and 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene was studied in V79 Chinese hamster fibroblasts after supplementations with arachidonic acid or treatments with linoleic acid hydroperoxide. The extent of metabolic activation was estimated using cytotoxicity and mutagenesis as endpoints. Pretreatment of cells with arachidonic acid for 24 h resulted in significant elevations in the content of this fatty acid in cell phospholipids and increased prostaglandin synthesis. Arachidonic acid and linoleic acid hydroperoxide facilitated 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene cytotoxicity and mutagenesis, and to a lesser extent increased the cytotoxicity and mutagenicity of benzo[a]pyrene. No other compounds tested were mutagenic under these conditions, however, linoleic acid hydroperoxide markedly increased their cytotoxicity. Arachidonic acid-facilitated toxicity and mutagenesis was inhibited by indomethacin, whereas no inhibition was seen when linoleic acid hydroperoxide was used. Nordihyroquairaretic acid abolished the cytotoxicity and mutagenesis facilitated by arachidonic acid and linoleic acid hydroperoxide. Our findings demonstrate that induction of cytotoxicity and mutagenesis following treatment of V79 cells with carcinogens may be limited by low levels of arachidonic acid in these cells. A peroxidatic mechanism is proposed, with limited substrate specificity, for the metabolic activation of chemicals in V79 cells.
Sevanian
A
A
University of Southern California, Institute for Toxicology, Los Angeles 90033.
Peterson
H
H
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004101:Dihydroxydihydrobenzopyrenes / Q000493:pharmacokinetics / Q000633:toxicity*; D015232:Dinoprostone / Q000032:analysis; D005227:Fatty Acids / Q000378:metabolism; D007975:Leukotriene B4 / Q000032:analysis; D008041:Linoleic Acids / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology; D009153:Mutagens; D009154:Mutation; D010544:Peroxidases / Q000378:metabolism*; D013929:Thromboxane B2 / Q000032:analysis; D015262:Xenobiotics / Q000493:pharmacokinetics
D001095:Arachidonic Acids; D004101:Dihydroxydihydrobenzopyrenes; D005227:Fatty Acids; D008041:Linoleic Acids; D008054:Lipid Peroxides; D009153:Mutagens; D015262:Xenobiotics; C017228:benzo(a)pyrene 7,8-dihydrodiol; D007975:Leukotriene B4; C008285:linoleic acid hydroperoxide; D001564:Benzo(a)pyrene; D013929:Thromboxane B2; D010544:Peroxidases; D015232:Dinoprostone