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The Liver-Selective Nitric Oxide Donor O²-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) Protects HepG2 Cells against Cytochrome P450 2E1-Dependent Toxicity

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York

HepG2 cells expressing CYP2E1 (E47 cells) are more susceptible to toxicity by arachidonic acid (AA) or after glutathione depletion with an inhibitor of glutamate-cysteine ligase, L-buthionine-(S,R)-sulfoximine (BSO), compared with control HepG2 cells (C34 cells). The ability of nitric oxide (NO) to protect against CYP2E1-dependent toxicity has not been evaluated. We therefore studied the ability of O²-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective NO donor, to protect against CYP2E1-dependent toxicity and compared this with protection by chemical NO donors. E47 cells incubated with V-PYRRO/NO produced NO, whereas C34 cells did not. Incubation of E47 cells with 50 µM AA or 100 µM BSO for 2 days resulted in a 50% loss of cell viability. VPYRRO/NO (1 mM) blocked this toxicity of AA and BSO by a mechanism involving NO release via CYP2E1 metabolism of VPYRRO/NO. NO scavengers hemoglobin and 2-(4-carboxophenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide blocked the protective effects of V-PYRRO/NO. V-PYRRO/NO inhibited CYP2E1 activity and production of reactive oxygen species, whereas hemoglobin prevented these events. AA and BSO induced lipid peroxidation and decreased mitochondrial membrane potential; both of these effects were blocked by V-PYRRO/NO. Unlike V-PYRRO/NO, the chemical donors spermine/NO and (S)-nitroso-N-acetylpenicillamine release NO directly when added to the medium; however, they could partially protect against the CYP2E1-dependent toxicity. These results suggest that VPYRRO/NO protects HepG2 cells against CYP2E1-dependent toxicity through inhibition of CYP2E1-derived reactive oxygen species production and lipid peroxidation by the generated NO and that this compound may be valuable in protecting against CYP2E1-dependent toxicity via liver P450-specific generation of NO.

Address correspondence to: Dr. Arthur Cederbaum, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1020, New York, NY 10029. E-mail: arthur.cederbaum{at}mssm.edu

This article has been cited by other articles:

				C. Edwards, H.-Q. Feng, C. Reynolds, L. Mao, and D. C. Rockey Effect of the nitric oxide donor V-PYRRO/NO on portal pressure and sinusoidal dynamics in normal and cirrhotic mice Am J Physiol Gastrointest Liver Physiol, June 1, 2008; 294(6): G1311 - G1317. [Abstract] [Full Text] [PDF]

				D. Wu and A. Cederbaum Glutathione Depletion in CYP2E1-Expressing Liver Cells Induces Toxicity Due to the Activation of p38 Mitogen-Activated Protein Kinase and Reduction of Nuclear Factor-{kappa}B DNA Binding Activity Mol. Pharmacol., September 1, 2004; 66(3): 749 - 760. [Abstract] [Full Text] [PDF]