Antioxidant and pro-oxidant effects of a manganese porphyrin complex against CYP2E1-dependent toxicity.
Superoxide dismutases (SOD) mimetics have been shown to be protective against cell injury caused by reactive oxygen species. The objective of this study was to investigate the effects of the manganese (III) tetrakis(N-methyl-2-pyridyl)porphyrin (MnTMPyP) on CYP2E1-dependent toxicity. The synergistic toxicity of iron and arachidonic acid has been associated with oxidative stress and lipid peroxidation in HepG2 cells that overexpress CYP2E1. Iron plus arachidonic acid caused loss of viability, increased lipid peroxidation and reactive oxygen species generation, and mitochondrial membrane injury in these cells. MnTMPyP partially protected against the decrease in cell viability, the enhanced lipid peroxidation and oxygen radical production, and the loss of mitochondrial membrane potential. The effect of MnTMPyP on arachidonic acid (absence of iron) toxicity was also evaluated. Arachidonic acid also caused toxicity, lipid peroxidation and reduction of the mitochondrial membrane potential. However, in this model, all of these alterations were actually enhanced by MnTMPyP. MnTMPyP also enhanced toxicity in CYP2E1-expressing HepG2 cells depleted of reduced glutathione (GSH). MnCl(2) had little or no effect on the toxicity by arachidonic acid, and MnTMPyP itself did not peroxidize arachidonic acid. MnTMPyP, an SOD mimetic that also scavenges hydrogen peroxide and peroxynitrite, thus showed an antioxidant and protective effect against iron plus arachidonic acid toxicity, but a pro-oxidant and cytotoxic effect against arachidonic acid toxicity in CYP2E1-expressing cells. These different actions may relate to the ability of MnTMPyP to either scavenge or produce free radicals in cells depending upon the prevailing MnTMPyP oxidation-reduction pathways. MnTMPyP and related manganese porphyrin compounds may have potential clinical utility against diseases associated with the overproduction of reactive oxygen species such as ethanol-induced liver injury but it is clear that further investigation of all the pathways of manganese porphyrin oxidation-reduction are necessary.
Pérez
María José
MJ
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cederbaum
Arthur I
AI
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D016718:Arachidonic Acid / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008345:Manganese; D008665:Metalloporphyrins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D000975:Antioxidants; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D008345:Manganese; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione