title: The role of redox cycling versus arylation in quinone-induced mitochondrial dysfunction: a mechanistic approach in classifying reactive toxicants.
abstract: In an attempt to distinguish between the mechanisms by which electrophilic and redox cycling quinones induce the cyclosporine A (CyA)-sensitive mitochondrial membrane permeability transition, the ability of a series of quinones that span a broad range of electrophilic and redox cycling reactivities has been examined. The order of potency of quinone-induced Ca2+ release was 1,4-naphthoquinone (NQ) > 1,4-benzoquinone (BQ) > 2-methyl-1,4-naphthoquinone (MQ) > 2,3-dimethoxy-1,4-naphthoquinone (DiOMeNQ) > 2,3-dimethyl-1,4-naphthoquinone (DiMeNQ). Quinones with predominantly redox cycling reactivity, NQ ( < or = 4 microM), MQ, DiOMeNQ and DiMeNQ, induced the CyA-sensitive membrane permeability transition. In contrast, NQ ( > 4 microM) and BQ, induced rapid and complete Ca2+ release and membrane depolarization, but not swelling. Furthermore, BQ and NQ ( > 4 microM)-induced effects were not prevented by CyA. Therefore, we maintain that, unlike MQ, DiOMeNQ, DiMeNQ and NQ ( < or = 4 microM), effects of BQ and NQ( > 4 microM) on calcium flux and membrane potential are manifest via a mechanism independent of altering the regulation of the cyclosporine A-sensitive PTP. These findings suggest that stereoelectronic descriptors for soft electrophilicity and one electron reduction potential may be useful in differentiating and predicting mechanisms of quinone toxicity.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Minnesota, Duluth 55812, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Henry
authors.forename: K B
authors.initials: KB
authors.lastname: Wallace
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000633:toxicity; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D011809:Quinones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016227:Benzoquinones; D009285:Naphthoquinones; D011809:Quinones; D016572:Cyclosporine; D002118:Calcium