Hepatic Disposition of Electrophilic Acyl Glucuronide Conjugates

Abstract

Acyl glucuronides are a unique class of electrophilic metabolites, capable of non-enzymatic reactions including acylation and/or glycation of endogenous macromolecules, hydrolysis to reform the parent aglycone, and intra-molecular rearrangement. Three human UDP-glucuronosyltransferases (UGTs) catalyzing the hepatic glucuronidation of carboxylic acid drugs have been identified, UGT1A3, UGT1A9 and a UGT2B7 variant. Within the liver, acyl glucuronides also undergo enzymatic hydrolysis by beta-glucuronidase and esterases which, like the UGTs, are located in the endoplasmic reticulum. In addition, the liver also transports acyl glucuronides between the sinusoidal circulation and bile. Due to their polarity, membrane transport of acyl glucuronides is carrier-mediated, resulting in the establishment of significant concentration gradients between sinusoidal circulation, hepatocyte and bile, in the order of 1:50:5,000 in these compartments, respectively. As a result of exposure to high acyl glucuronide concentrations, the liver is a major target of protein adduct formation. Dipeptidylpeptidase IV, UGTs and tubulin have been identified as intra-hepatic targets of adduct formation by acyl glucuronides. Adduct formation results in altered protein activity and potentially contributes to hepatotoxicity. Hepatic protein adducts are also immunogenic and may cause immune mediated cytotoxicity. Both intra- and extra-hepatic exposure to acyl glucuronides depends not only on the efficiency of glucuronidation and hydrolysis by the liver, but also on the efficiency of the hepatic membrane transport systems. Thus, changes in membrane transporter activities, as may occur due to saturation or drug-drug interactions, can significantly affect acyl glucuronide disposition, adduct formation and the disposition of parent aglycone, thereby affecting clinical efficacy and toxicity of acyl glucuronide forming drugs.

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

“…Once excreted into the intestines, DF glucuronides can be hydrolyzed by bacterial ␤-glucuronidases, and reabsorption of DF results in significant enterohepatic circulation (Peris-Ribera et al, 1991;. However, acyl glucuronides are chemically unstable and can undergo epimerization by acyl migration to the 2-, 3-, or 4-O-glucuronide, especially in the alkaline environment of bile, and these isomers are believed to be resistant to cleavage by bacterial ␤-glucuronidases (Dickinson and King, 1991;Ding et al, 1993;Sallustio et al, 2000).…”

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

“…DCF-AG is initially formed as a b-1-O-acyl glucuronide (b-anomer), which can be cleaved by b-glucuronidase into DCF and glucuronic acid. b-Anomers spontaneously isomerize into b-glucuronidase-resistant 2-, 3-, and 4-O-acyl isomers (Sallustio et al, 2000). DCF-AG undergoes these rearrangements as the pH changes from acidic to physiologic conditions such as those that occur in the GI tract (Ebner et al, 1999;Kenny et al, 2004).…”

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic GlutathioneS-Transferases

“…Thus, various acylglucuronides have been shown to be electrophilic metabolites that can spontaneously react with proteins both in vitro and in vivo, leading to adduct formation (Sallustio et al, 2000). This reactivity is not limited to proteins because electrophilic acylglucuronide conjugates have been reported to react with the tripeptide glutathione,…”