Differential mechanisms of cell killing by redox cycling and arylating quinones.
The role of mitochondrial dysfunction in the mechanisms of cell killing by quinones of differing chemical reactivities was investigated. Freshly isolated hepatocyte suspensions were exposed to 2,3-dimethoxy-1,4-naphthoquinone, 2-methyl-1,4-naphthoquinone, 1,4-naphthoquinone or 1,4-benzoquinone in the presence or absence of cyclosporine A, ruthenium red, fructose or the combination of fructose plus oligomycin. All of the quinones caused concentration-dependent cell killing as assessed by the leakage of lactate dehydrogenase. However, only 2,3-dimethoxy- and 2-methyl-naphthoquinone caused a depolarization of mitochondrial membrane potential; cell killing by 1,4-naphthoquinone or 1,4-benzoquinone was not accompanied by mitochondrial depolarization. Neither cyclosporine A nor ruthenium red protected against cell killing or loss of mitochondrial membrane potential caused by any of the quinones examined. In contrast, fructose protected cells against all four quinones. For the redox cycling naphthoquinones, oligomycin reversed the protection afforded by fructose. However, the cytoprotective effect of fructose against the arylating quinones, 1,4-naphthoquinone and 1,4-benzoquinone, was not reversed by oligomycin. The results suggest that cell killing by redox cycling naphthoquinones is a manifestation of mitochondrial depolarization, not ATP depletion. In contrast, the fructose-mediated protection from arylating quinones is consistent with ATP depletion being a critical event leading to cell death. According, although a vast array of quinone compounds are known to be cytotoxic, the mechanism of cell killing by individual members of this chemical class differs and is determined primarily by the chemical reactivity of the individual quinone.
Henry
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TR
Department of Pharmacology, University of Minnesota, School of Medicine, Duluth 55812, USA.
Wallace
K B
KB
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D009285:Naphthoquinones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D024483:Vitamin K 3
D009285:Naphthoquinones; C063002:2,3-dimethoxy-1,4-naphthoquinone; D024483:Vitamin K 3; C035342:1,4-naphthoquinone