Role of p38 MAPK in CYP2E1-dependent arachidonic acid toxicity.
Polyunsaturated fatty acids such as arachidonic acid (AA) play an important role in alcohol-induced liver injury. AA promotes toxicity in rat hepatocytes with high levels of cytochrome P4502E1 (CYP2E1) and in HepG2 E47 cells, which express CYP2E1. The possible role of mitogen-activated protein kinase (MAPK) members in this process was evaluated. SB203580, a p38 MAPK inhibitor, and PD98059, an ERK inhibitor, but not wortmannin a phosphatidylinositol 3-kinase (PI3K) inhibitor, prevented AA toxicity in pyrazole hepatocytes and E47 cells. SB203580 prevented the enhancement of AA toxicity by salicylate. SB203580 neither lowered the levels of CYP2E1 nor affected CYP2E1-dependent oxidative stress. The decrease in mitochondrial membrane potential produced by AA was prevented by SB203580. Treating CYP2E1-induced cells with AA activated p38 MAPK but not ERK or AKT. This activation was blocked by antioxidants. AA increased the translocation of NF-kappaB to the nucleus. Salicylate blocked this translocation, which may contribute to the enhancement of AA toxicity by salicylate. SB203580 restored AA-induced NF-kappaB translocation, which may contribute to protection against toxicity. In conclusion, AA toxicity was related to lipid peroxidation and oxidative stress, and to the activation of p38 MAPK, as a consequence of CYP2E1-dependent production of reactive oxygen species. Activation of p38 MAPK by AA coupled to AA-induced oxidative stress may synergize to cause cell toxicity by affecting mitochondrial membrane potential and by modulation of NF-kappaB activation.
Wu
Defeng
D
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York University, New York 10029, USA.
Cederbaum
Arthur I
AI
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000633:toxicity*; D002460:Cell Line; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D005419:Flavonoids; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D012459:Salicylates; D016718:Arachidonic Acid; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one