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Antioxidant and pro-oxidant effects of a manganese porphyrin complex against CYP2E1-dependent toxicity.
Free Radic Biol Med. 2002 Jul 01; 33(1):111-27.FR

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12086689

Citation

Pérez, María José, and Arthur I. Cederbaum. "Antioxidant and Pro-oxidant Effects of a Manganese Porphyrin Complex Against CYP2E1-dependent Toxicity." Free Radical Biology & Medicine, vol. 33, no. 1, 2002, pp. 111-27.
Pérez MJ, Cederbaum AI. Antioxidant and pro-oxidant effects of a manganese porphyrin complex against CYP2E1-dependent toxicity. Free Radic Biol Med. 2002;33(1):111-27.
Pérez, M. J., & Cederbaum, A. I. (2002). Antioxidant and pro-oxidant effects of a manganese porphyrin complex against CYP2E1-dependent toxicity. Free Radical Biology & Medicine, 33(1), 111-27.
Pérez MJ, Cederbaum AI. Antioxidant and Pro-oxidant Effects of a Manganese Porphyrin Complex Against CYP2E1-dependent Toxicity. Free Radic Biol Med. 2002 Jul 1;33(1):111-27. PubMed PMID: 12086689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antioxidant and pro-oxidant effects of a manganese porphyrin complex against CYP2E1-dependent toxicity. AU - Pérez,María José, AU - Cederbaum,Arthur I, PY - 2002/6/28/pubmed PY - 2003/1/11/medline PY - 2002/6/28/entrez SP - 111 EP - 27 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 33 IS - 1 N2 - 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. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/12086689/Antioxidant_and_pro_oxidant_effects_of_a_manganese_porphyrin_complex_against_CYP2E1_dependent_toxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891584902008651 DB - PRIME DP - Unbound Medicine ER -