Oltipraz-induced phase 2 enzyme response conserved in cells lacking mitochondrial DNA.
Oltipraz, a member of a class of 1,2-dithiolethiones, is a potent phase 2 enzyme inducing agent used as a cancer chemopreventive. In this study, we investigated regulation of the phase 2 enzyme response and protection against endogenous oxidative stress in lymphoblastic leukemic parental CEM cells and cells lacking mitochondrial DNA (mtDNA) (rho0) by oltipraz. Glutathione (GSH) levels (total and mitochondrial) and glutathione S-transferase (GST) activity were significantly increased after pretreatment with oltipraz in both parental (rho+) and rho0 cells, and both cell lines were resistant to mitochondrial oxidation, loss of mitochondrial membrane potential, and cell death in response to the GSH depleting agent diethylmaleate. These results show that the phase 2 enzyme response, by enhancing GSH-dependent systems involved in xenobiotic metabolism, blocks endogenous oxidative stress and cell death, and that this response is intact in cells lacking mtDNA.
Chua
Yee Liu
YL
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
Zhang
Dawei
D
Boelsterli
Urs
U
Moore
Philip K
PK
Whiteman
Matthew
M
Armstrong
Jeffrey S
JS
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D004272:DNA, Mitochondrial; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D005982:Glutathione Transferase; D005978:Glutathione