UDP-Glucuronyltransferases and Their Toxicological Significance

Abstract

In general chemicals are converted by phase-I enzymes of drug metabolism to a variety of nucleophilic and electrophilic metabolites (Fig. 1). The interaction of the more reactive electrophilic metabolites with critical cellular macromolecules plays a major role in their toxicity (Miller and Miller, 1981). Therefore much interest was given to the control of electrophilic metabolites. However the more stable and more abundant nucleophilic metabolites can also be readily converted to reactive metabolites. For example studies on benzene toxicity have shown that the major primary metabolite phenol is further oxidized to quinols, catechol and hydroquinone, in liver. These quinols are accumulating in bone marrow where they may be further oxidized to radical intermediates (Greenlee et al., 1981). Similarly, benzo(a)pyrene (BP) quinols are readily converted to reactive semiquinones. Moreover they undergo toxic redox-cycles between quinones and quinols with a continuous generation of reactive oxygen species (Lorentzen and Ts’o, 1977; Lorentzen et al., 1979; Lilienblum et al., 1985). Therefore the control of nucleophilic metabolites by UDP-glucuronyltransferase (GT) and sulfotransferase cannot be neglected. In the case of benzene toxicity conjugation leads to the elimination of quinols. In support of this observation the time course of induction of UDP-glucuronyltransferase (GT) by 3,4,3′,4′-tetrachlorobiphenyl mirrored the time course of protection against benzene toxicity in the bone marrow and lymphoid organs (Greenlee and Irons, 1981). In this context it is to be noted that some conjugates, in particular sulfate esters, are more reactive than the parent compounds (Miller and Miller, 1978).