The Role of Redox Cycling Versus Arylation in Quinone-Induced Mitochondrial Dysfunction: A Mechanistic Approach in Classifying Reactive Toxicants

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 (< 4pM), MQ, DiOMeNQ and DiMeNQ, induced the CyA-sensitive membrane permeability transition. In contrast, NQ (>4pM) and BQ, induced rapid and complete Ca2+ release and membrane depolarization, but not swelling. Furthermore, BQ and NQ (> 4 pM)-induced effects were not prevented by CyA. Therefore, we maintain that, unlike MQ, DiOMeNQ, DiMeNQ and NQ (<4pM), effects of BQ and NQ(>4pM) 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.