Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes.

The widespread belief that oxidative damage plays a major role in cancer, ageing, and in a number of chronic diseases has focused scienti®c and public attention on the possibility that antioxidants could prevent or at least retard these processes. Antioxidants are of two types: direct and indirect. Direct antioxidants [e.g. glutathione (GSH), tocopherols, ascorbic acid and carotenoids] are substances that can participate in physiological, biochemical or cellular processes that inactivate free radicals or that prevent free-radical initiated chemical reactions. Direct antioxidants may also exhibit prooxidant eects under some experimental conditions, but whether these properties play a signi®cant role in vivo remains unclear. In contrast, indirect antioxidants are not able to participate in radical or redox reactions as such, but they boost the antioxidant capacity of cells by a variety of mechanisms described below, and thereby aord protection against oxidative stress. There is substantial and mounting evidence that Phase II enzymes [e.g. glutathione transferases (GSTs), NAD(P)H:quinone reductase (QR), epoxide hydrolase, heme oxygenase, UDP-glucuronosyltransferase] play important roles in the detoxication of electrophiles and their induction protects animals and their cells against carcinogenesis and mutagenesis (Benson et al., 1978, 1980; Kensler, 1997; Prestera et al., 1995; Talalay, 1992). The prevailing view of the mechanisms responsible for the protective functions of Phase II enzyme inducers has focused on the abilities of these enzymes to detoxify reactive electrophiles, and the inductive process has been termed the ``electrophile counterattack response'' (Prestera et al., 1993). In this paper, we marshall evidence that a very important but largely ignored consequence of Phase II enzyme induction is the enhancement of cellular antioxidant capacity. There is now considerable information on the chemistry of inducers. Eight classes of chemical agents have been identi®ed as inducers of Phase II enzymes (Prestera et al., 1993; Talalay et al., 1988): (1) diphenols, phenylenediamines, and quinones; (2) Michael reaction acceptorsÐcompounds containing ole®n or acetylene linkages conjugated to electron-withdrawing groups; (3) isothiocyanates; (4) hydroperoxides and hydrogen peroxide; (5) 1,2-dithiole-3-thiones; (6) vicinal dimercaptans; (7) trivalent arsenicals; (8) divalent heavy metals. These inducers vary greatly in potencies and show little structural similarity, but are all chemically reactive with sulfhydryl groups, and most are also substrates for GSTs (Prestera et al., 1993; Spencer et al., 1991). Recently, a ninth class of inducers comprising carotenoids, curcumins and related polyenes has been added (Dinkova-Kostova and Talalay, 1999; Khachik et al., 1999). Inducers of Phase II enzymes also raise the activity of g-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis, and thereby elevate tissue GSH levels (Mulcahy et al., 1997). It is of interest that several of the types of aforementioned inducers of Food and Chemical Toxicology 37 (1999) 973±979