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Vol. 59, Issue 4, 795-805, April 2001

Sodium Salicylate Increases CYP2E1 Levels and Enhances Arachidonic Acid Toxicity in HepG2 Cells and Cultured Rat Hepatocytes

Defeng Wu and Arthur I. Cederbaum

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine of New York University, New York, New York

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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