The metabolism of quinone-containing alkylating agents: Free radical production and measurement

The metabolism of quinone-containing antitumor agents involves enzymatic re duction of the quinone by one or two electrons. This reduction results in t he formation of the semiquinone or the hydroquinone of the anticancer drug. The consequence of these enzymatic reductions is that the semiquinone yiel ds its extra electron to oxygen with the formation of superoxide radical an ion and the original quinone. This reduction by a reductase followed by oxi dation by molecular oxygen (dioxygen) is known as redox-cycling and continu es until the system becomes anaerobic. In the case of a two electron reduct ion, the hydroquinone could become stable, and as such, excreted by the org anism in a detoxification pathway. In some cases such as aziridine quinones , the hydroquinone can be oxidized by one electron at a time resulting in t he production of superoxide, the semiquinone and the parental quinone. Quin one anticancer agents upon reduction can also set up an equilibrium between the hydroquinone, the parental quinone and the semiquinone which results i n a long-lived semiquinone. Depending on the compound, aziridine quinones, for example, this equilibrium is long lasting thus allowing for the detecti on of the semiquinone under aerobic conditions. This phenomenon is known as comproportionation-disporportionation equilibrium. The series of reviews i n this Special Issue address the consequences of bioreduction of quinone al kylators used in the treatment of cancer. In this particular review we are interested in describing the phenomenon of redox-cycling, how it is measure d, and the biological consequences of the presence of the semiquinone and t he oxygen radicals generated.