Free Radical Formation in the Reactions of Redox-Active Drugs and Xenobiotics with Mitochondrial Flavoenzymes

The single-electron reduction of redox-active drugs and xenobiotics (quinones, aromatic nitrocompounds, and N-oxides) by flavoenzymes, which initiates redox cycling and oxidative stress, is an important factor in their therapeutic/toxic effects. This review summarizes information on the action of mitochondrial flavoenzymes from various organisms in these processes, emphasizing the kinetic and mechanistic aspects. The flavoenzymes discussed also include those of which only a fraction is localized in mitochondria. According to kinetic data, the most effective generator of free radicals of xenobiotics is respiratory Complex I. However, it is unclear to what extent these reactions can compete with the rapid reduction of ubiquinone in normally functioning mitochondria. In specific cases, a very active free radical generator can be the NADPH:adrenodoxin reductase-adrenodoxin complex. The properties of other dehydrogenases-electrontransferases (succinate:ubiquinone reductase, fatty acid oxidation system) are less well characterized. Due to its high catalytic capacity, a potential but poorly studied source of free radicals of xenobiotics may be NADH:cytochrome b₅ reductase and its complex with cytochrome b₅. Flavoenzyme disulfide reductases, with the possible exception of Plasmodium falciparum thioredoxin reductase, are less active free radical generators. Importantly, in most cases, flavoenzymes perform the mixed single- and two-electron reduction of xenobiotics. According to the available data, the reactivity of redox cyclers depends mostly on their standard single-electron reduction potential and is little influenced by their structure. Therefore, in order to intensify these processes or achieve some structural specificity, it is necessary to focus on the selective accumulation of compounds in mitochondria.