Glucuronidation-dependent toxicity and bioactivation

Abstract

Due to their polarity and hydrophilicity, glucuronide conjugates do not readily diffuse across biological membranes, and their uptake into, and efflux out of, cells requires the action of membrane transporters. This fundamental property of glucuronide conjugates, coupled with Mrp2/MRP2-mediated cellular efflux, underpins the role of glucuronidation in facilitating the excretion of endogenous and exogenous compounds, thus completing the detoxification and deactivation cycle. However, it has also complicated our understanding of the in vivo and in vitro effects of pharmacologically active or reactive glucuronides, since exogenously pre-formed glucuronide conjugates are often tested for in vitro genotoxicity or cytotoxicity in cell systems that may lack appropriate uptake transporters, or are administered in vivo without taking into account their significantly different distribution compared to intra-cellularly generated metabolites. There are now numerous examples of glucuronide metabolites that retain pharmacological activity, that are bioactivation products, or that facilitate the transport of toxins to the gut or urinary tract. Our growing appreciation and understanding of the inter-relationship between UGT-catalysed metabolism and transporter-mediated cellular uptake and efflux will be essential to further assessing the contribution of glucuronidation to in vivo toxicity in humans and animals. © 2008 Elsevier B.V. All rights reserved.