Antioxidant and mitochondrial protective effects of oxidized metabolites of oltipraz.
BACKGROUND
Comprehensive studies indicate that oltipraz exerts cancer chemopreventive effects. Oltipraz has other therapeutic potentials, which include anti-fibrotic effect, inhibition of insulin resistance, mitochondrial protection and cytoprotective effect against oxidative stress. Although antioxidant mechanisms may account for its cancer chemopreventive effect, details on the molecular mechanism still remain to be clarified.


METHODS
Two major metabolic pathways of oltipraz include oxidative desulfuration of the thione to yield 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one and molecular rearrangement to 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine. In addition to the diverse pharmacological effects of oltipraz, the oxidized metabolites may have distinct biological effects on cell survival. The AMP-activated protein kinase pathway has been recognized as a key cascade for mitochondrial protection and cell survival events, which can be activated by the oxidized metabolites of oltipraz.


RESULTS
In this review, the metabolic activation of oltipraz and the role of the cell signaling pathways in regulating the expression of Phase II genes and antioxidant activity are discussed with particular reference to their effects on mitochondrial protection and cell survival.


CONCLUSIONS
In terms of therapeutic potential, the findings reviewed here demonstrate a therapeutic potential for oxidized metabolite of oltipraz and offer comparison of antioxidant capacity between metabolites and parent compound.
Choi
Song Hwa
SH
Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sillim-dong, Gwanak-gu, Seoul 151-742, Korea, Republic of Korea. sgk@snu.ac.kr
Kim
Young Mi
YM
Lee
Jung Min
JM
Kim
Sang Geon
SG
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D055372:AMP-Activated Protein Kinases