Glucuronidation: a dual control.

1. Glucuronidation is a major detoxication process catalyzed by uridine diphosphate glucuronosyltransferases. 2. The amount of enzyme can be modulated by numerous foreign compounds, such as common chemical inducers already implicated in the induction of other detoxication enzymes. 3. Hormones such as thyroid hormones or growth hormone also are implicated in the control of glucuronidation. 4. Because glucuronidation enzymes (isozymes) are anchored in the endoplasmic reticulum membrane, with their active site likely being located on the lumenal side of the membrane, the membrane environment of these enzymes was shown to modulate their functional state as evaluated by the conjugating activity per enzymatic molecular unit. 5. In accord with a first, previously proposed model, it seems that this modulation can be attributed to different conformational states of the enzymes, depending on the physicochemical state of the membrane. 6. In accord with a second model, the membrane may act as a barrier between the enzymes and the cosubstrate UDP-glucuronic acid, which is a polar and charged molecule synthesized in the cytosol. This would imply a transporting process for this molecule through the reticulum membrane, which has been characterized in vitro and could be of importance in vivo. 7. Glucuronidation is under the control of a dual regulation, by means of a specific isozyme expression level and by the modulation of their functional state.