Sodium salicylate increases CYP2E1 levels and enhances arachidonic acid toxicity in HepG2 cells and cultured rat hepatocytes.
Sodium salicylate and acetylsalicylic acid are drugs used as anti-inflammatory agents. Salicylate prevents nuclear factor-kappa B activation and can cause apoptosis. However, salicylate, a substrate of CYP2E1, is also an antioxidant and can scavenge reactive oxygen species. Experiments were carried out to evaluate whether salicylate can modulate CYP2E1-dependent toxicity. Addition of a polyunsaturated fatty acid such as arachidonic acid (AA) to HepG2 cells resulted in loss of cell viability, especially in cells expressing CYP2E1 (E47 cells). Toxicity was enhanced by the addition of 1 to 10 mM salicylate to the E47 cells but not to control HepG2 cells or HepG2 cells expressing CYP3A4. Salicylate alone was not toxic, and the enhanced toxicity by AA in the presence of salicylate was prevented by diallyl sulfide, a CYP2E1 inhibitor, and by the antioxidant (+/-)6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. Salicylate potentiated AA-induced lipid peroxidation in the E47 cells, a reaction blocked by diallyl sulfide. CYP2E1 levels were elevated by salicylate at concentrations (<5 mM), which did not increase CYP2E1 mRNA levels. This increase was associated with a decrease of CYP2E1 turnover by salicylate in the presence of cycloheximide. Salicylate also potentiated AA toxicity in hepatocytes isolated from pyrazole treated rats with high levels of CYP2E1 and from saline controls. In view of the potential role of CYP2E1 in contributing to alcohol-induced oxidative stress and liver injury, the potentiation of CYP2E1-dependent toxicity and the elevation of CYP2E1 levels by salicylate may be of clinical significance and merit caution in the use of salicylate and salicylate precursors such as acetylsalicylic acid with certain other drugs.
Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA.
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D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012980:Sodium Salicylate / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D000975:Antioxidants; D002839:Chromans; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D011500:Protein Synthesis Inhibitors; D011720:Pyrazoles; D012333:RNA, Messenger; D013440:Sulfides; D016718:Arachidonic Acid; C031280:pyrazole; C038491:allyl sulfide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D012980:Sodium Salicylate