Oxidative damage to mitochondria and protection by ebselen and other antioxidants.
Iron/ascorbate induced lipid peroxidation in liver mitochondria isolated from normal and glutathione-depleted rats was monitored by low-level chemiluminescence and by accumulation of thiobarbituric acid-reactive substances (TBARS). Antioxidant capacity was assessed by the duration of the lag phase preceding the onset of active peroxidation. The lag phases in state 4 and in the presence of uncouplers were similar, but shorter in the presence of ADP (state 3). In glutathione-depleted rats the lag periods were less than those in normal mitochondria. A biphasic pattern of loss of membrane alpha-tocopherol was typical in state 4 with about 55% remaining after 40 min, while in presence of ADP there was a steady and rapid loss to about 30% of the initial level. Synthetic antioxidants such as ebselen or its glutathione adduct protected mitochondrial membranes against peroxidative reactions. There was a 5-fold increase in the lag phase with 1 microM ebselen in state 4 (lag doubling concentration, 0.4 microM) and a significantly lower rate of loss of alpha-tocopherol with about 90% of the initial level still remaining after 40 min. Likewise, the lag doubling concentrations were 0.04 microM for diethyldithiocarbamate, 0.3 microM for 5-hydroxyindole, 10 microM for dihydroxyphenylalanine and serotonin, and about 40 microM for epinephrine and norepinephrine.
Narayanaswami
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Institut für Physiologische Chemie I, Universität Düsseldorf, Federal Republic of Germany.
Sies
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H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000172:deficiency / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects; D054833:Isoindoles; D015227:Lipid Peroxidation / Q000187:drug effects*; D008163:Luminescent Measurements; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D016566:Organoselenium Compounds; D051381:Rats; D012643:Selenium / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014810:Vitamin E / Q000378:metabolism
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D013844:Thiazoles; D014810:Vitamin E; C060674:2-phenyl-1,2-benzisothiazol-3-(2H)-one; C042986:ebselen; D004050:Ditiocarb; D005978:Glutathione; D012643:Selenium