Cutaneous NAD(P)H: quinone reductase: a xenobiotica-metabolizing enzyme with potential cancer and oxidation stress-protecting properties.

The toxicity of quinones--including certain chemotherapeutic agents such as doxorubicin--have been related to the enzymatic or nonenzymatic formation of the corresponding semiquinones and their subsequent reaction with molecular oxygen yielding superoxide anion radicals by spontaneous regenerating of the quinones. This semiquinone redox cycling is prevented by the NAD(P)H:quinone reductase (NQR; EC 1.6.99.2) because it mediates a 2-electron reduction which results in the formation of hydroquinones instead of semiquinones. Interestingly, inducers of this enzyme such as butylated hydroxytoluene protect against the severe ulceration of accidental infiltration of doxorubicin into the area around the intravenous infusion. Recently, it has been shown that this highly protective enzyme has a very high basal activity in the epidermis which is in the same range as in the liver. The human gene of the NQR is localized on chromosome 16 and has been cloned recently as well as the gene of the murine liver NQR. We determined NQR in the cytoplasma of murine skin, liver, and human keratinocytes using 2,6-dichlorophenol-indophenol as substrate. In order to characterize this enzyme, induction by polycyclic hydrocarbones and inhibition with several known inhibitors of dihydrodiol dehydrogenase, aldo-keto and carbonyl reductase activities were determined. There was a similar pattern of inhibition of the basal and induced activity in all tissues so far investigated. Pyrazole, progesterone and phenobarbital did not inhibit; however, rutin and indomethacin inhibited dose-dependently. The most potent inhibitor was dicoumarol. These findings suggest that the same enzymatic form is present in liver and skin, and in murine skin and human keratinocytes.