In this work, the topology of mitochondrial O2(-)(radical) and H2O2 generation and their interplay with matrix GSH in isolated heart mitochondria were examined. We observed that complex I releases O2(-)(radical) into the matrix (where it is converted to H2O2 by Mn-SOD) but not into the intermembrane space. No free radical generation was observed from complex II, but succinate treatment caused H...

Poor local control and tumor escape are of major concern in head-and-neck cancers treated by conventional radiotherapy or hadrontherapy. Reduced glutathione (GSH) is suspected of playing an important role in mechanisms leading to radioresistance, and its depletion should enable oxidative stress insult, thereby modifying the nature of DNA lesions and the subsequent chromosomal changes that poten...

Allyl isothiocyanate (AITC) is a phytochemical associated with plant defense in plants from the Brassicaceae family. AITC has long been recognized as a countermeasure against external threats, but recent reports suggest that AITC is also involved in the onset of defense-related mechanisms such as the regulation of stomatal aperture. However, the underlying cellular modes of action in plants rem...

The redox environment in cells and organisms is set by low-molecular mass and protein-bound thiols, with glutathione (GSH) representing a major intracellular redox buffer. Subtle thiol oxidation elicits signal transduction processes and adaptive responses to cope with stressors, whereas highly oxidizing conditions may provoke cell death. We here tested how thiol depletion affects life span, str...

Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4,ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD(0), which is present in the other MRPs. Using cells stably...

Methamphetamine- (MA-) induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. Our previous study demonstrated that MA induces autophagy in a dopaminergic neuronal cell model (N27 cells). The cellular mechanisms underlying MA-induced autophagy and apoptosis remain poorly characterized. In the present study we sought to investigate the importance of GSH ...

We developed a LC-MS-MS assay of the (2)H labeling of free glutathione (GSH) and bound glutathione [GSSR; which includes all DTT-reducible forms, primarily glutathione disulfide (GSSG) and mixed disulfides with proteins] and ophthalmate (an index of GSH depletion) labeled from (2)H-enriched body water. In rats whose body water was 2.5% (2)H enriched for up to 31 days, GSH labeling follows a com...

Kombu RS, Zhang GF, Abbas R, Mieyal JJ, Anderson VE, Kelleher JK, Sanabria JR, Brunengraber H. Dynamics of glutathione and ophthalmate traced with H-enriched body water in rats and humans. Am J Physiol Endocrinol Metab 297: E260–E269, 2009. First published April 28, 2009; doi:10.1152/ajpendo.00080.2009.—We developed a LC-MS-MS assay of the H labeling of free glutathione (GSH) and bound glutathi...

Parkinson's disease (PD) is characterized by degeneration of dopamine (DA)-containing nigro-striatal neurons. Loss of the antioxidant glutathione (GSH) has been implicated in the pathogenesis of PD. Previously, we showed that the oxidant hydrogen peroxide inhibits vesicular uptake of DA in nigro-striatal neurons. Hydrogen peroxide is scavenged by GSH and, therefore, we investigated a possible l...

Glutathione (GSH) plays a crucial role in the protection of normal and tumor tissue against the toxic effects of numerous chemotherapeutic drugs. Therefore, the possible therapeutic benefit of thiol depletion in cancer treatment is dependent upon the relative degree to which tumor or normal tissue is sensitized to the toxic effects of subsequent chemotherapy. To address this issue, the followin...