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-inflammat ory agents. Salicylate prevents nuclear factor-kappaB activation and can ca use apoptosis. However, salicylate, a substrate of CYP2E1, is also an antio xidant and can scavenge reactive oxygen species. Experiments were carried o ut to evaluate whether salicylate can modulate CYP2E1-dependent toxicity. A ddition of a polyunsaturated fatty acid such as arachidonic acid (AA) to He pG2 cells resulted in loss of cell viability, especially in cells expressin g CYP2E1 (E47 cells). Toxicity was enhanced by the addition of 1 to 10 mM s alicylate to the E47 cells but not to control HepG2 cells or HepG2 cells ex pressing CYP3A4. Salicylate alone was not toxic, and the enhanced toxicity by AA in the presence of salicylate was prevented by diallyl sulfide, a CYP 2E1 inhibitor, and by the antioxidant (+/-)6-hydroxy-2,5,7,8-tetramethylchr oman-2-carboxylic acid. Salicylate potentiated AA-induced lipid peroxidatio n in the E47 cells, a reaction blocked by diallyl sulfide. CYP2E1 levels we re 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 p otentiated AA toxicity in hepatocytes isolated from pyrazole treated rats w ith high levels of CYP2E1 and from saline controls. In view of the potentia l role of CYP2E1 in contributing to alcohol-induced oxidative stress and li ver injury, the potentiation of CYP2E1-dependent toxicity and the elevation of CYP2E1 levels by salicylate may be of clinical significance and merit c aution in the use of salicylate and salicylate precursors such as acetylsal icylic acid with certain other drugs.