Advances in research on DT-diaphorase--catalytic properties, regulation of activity and significance in the detoxication of foreign compounds.

Abstract

DT-diaphorase [NAD(P)H dehydrogenase (quinone), EC 1.6.99.2] is a flavoprotein enzyme widely distributed in the cytosolic fractions of various animal tissues. It is also called menadione reductase or NAD(P)H-quinone reductase and catalyzes NAD(P)H-dependent 1-, 2- or 4-electron reduction of certain redox dyes, aromatic nitro compounds, aromatic C-nitroso compounds and probably azo-dyes, as well as menadione (vitamin K3) and other quinones. Dicumarol exerts characteristic inhibition on DT-diaphorase, whereas serum albumin and certain non-ionic detergents exert activation. Excessive concentrations of many of the electron acceptors inhibit the activity of this enzyme. The physiological significance of DT-diaphorase is still obscure because the physiological vitamins (K1 and K2) and coenzyme Q10 are difficult to reduce with this enzyme. Results of recent studies suggest that DT-diaphorase prevents formation of active oxygen species. Activities in liver and other tissues are known to be enhanced by administration of chemicals including certain carcinogens such as 3-methylcholanthrene (3-MC), anti-oxidants such as 3-tert-butyl-4-hydroxyanisole (BHA), and other compounds. Both basal and induced activities vary considerably with tissue, sex, strain and species of animals. The strain variations in activities in rat and mouse liver are known to be inherited, and the trait of hereditary transmission can be adequately explained by postulating two loci of genes or gene clusters regulating the activity. Resistance of animals to various toxic or carcinogenic substances may be promoted by BHA administration and depressed by dicumarol administration. Thus, attention has been focused on the role played by DT-diaphorase in the detoxication of foreign compounds. Knowledge on strain variations in basal and induced activities of tissue DT-diaphorase is of potential value when choosing a rat or mouse strain suitable for studying the toxic effects of drugs, especially drugs expected to be detoxified by reductive metabolism. With future progress in research on DT-diaphorase, this enzyme might be applied to prophylactic and therapeutic medicine.