Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/14388
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Type: Journal article
Title: Hepatic disposition of electrophilic acyl glucuronide conjugates
Author: Sallustio, B.
Sabordo, L.
Evans, A.
Nation, R.
Citation: Current Drug Metabolism, 2000; 1(2):163-180
Publisher: Benthem Science Publishers
Issue Date: 2000
ISSN: 1389-2002
1875-5453
Statement of
Responsibility: 
B. C. Sallustio, L. Sabordo, A. M. Evans and R. L. Nation
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 b-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 150 5000 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.
Keywords: Hepatic disposition, electrophilic acyl, glucuronide conjugates, membrane tranport, canalicular efflux, basolateral efflux
Rights: © 2000 Bentham Science Publishers. All Rights Reserved.
RMID: 0001000689
DOI: 10.2174/1389200003339153
Appears in Collections:Pharmacology publications

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