Elsevier

Biochemical Pharmacology

Volume 55, Issue 7, 1 April 1998, Pages 1005-1012
Biochemical Pharmacology

Original Articles
Drug Glucuronidation by Human Renal UDP-Glucuronosyltransferases 1

https://doi.org/10.1016/S0006-2952(97)00534-0Get rights and content

Abstract

The UDP-glucuronosyltransferases catalyse the conjugation of glucuronic acid to a wide variety of endobiotics and xenobiotics, representing one of the major conjugation reactions in the conversion of both exogenous (e.g. drugs and pesticides) and endogenous compounds (e.g. bilirubin and steroid hormones). The liver is the major site of glucuronidation, however a number of extrahepatic tissues exhibit particular UDP-glucuronosyltransferase activities. The present study was undertaken to assess the human renal UDP-glucuronosyltransferase system. Enzymatic analysis of human kidney showed that a limited number of UDP-glucuronosyltransferase isoforms were expressed in this tissue. However the level of renal UGT activity towards the anaesthetic propofol was higher compared with human liver. The glucuronidation of propofol is catalysed by UGT1A8/9 suggesting higher levels of this isoform in the kidney. Immunoblot analysis revealed two major UDP-glucuronosyltransferase immunopositive bands to be present in human kidney as compared to four major bands in human liver. The human kidney was capable of conjugating various structurally diverse drugs and xenobiotics.

Section snippets

Materials

14C-UDP-glucuronic acid, UDPGA (≥303 Ci/mmol) was obtained from Dupont Ltd. 14C-1-Naphthol (59 mCi/mmol) was purchased from Amersham. Unlabelled UDPGA (triammonium salt) was purchased from Sigma Chemical Company. In addition, nitro blue tetrazolium, (NBT), 5-bromo-4-chloro-3-indolyl phosphate, (BCIP), bovine serum albumin, bilirubin and alkaline phosphatase-labelled anti-goat IgG (whole molecule) were obtained from Sigma. Nitrocellulose (Schleicher & Scheull, BA 85) was obtained from Anderman &

Drug and Xenobiotic Glucuronidation in Human Kidney Microsomes

The addition of lubrol to the microsomal membrane preparation increased the levels of 1-naphthol UGT activity (Fig. 1). Increasing amounts of lubrol in the membrane preparation ultimately inhibited this activity. This latency has previously been shown to regulate UGT activity at the level of the endoplasmic membrane [29]. Both human and rat kidney were activated approximately 3-fold with the addition of lubrol indicating similar regulation of renal UGT activity between species. The lubrol

Discussion

Glucuronides of many drugs and xenobiotics are excreted in urine. We therefore aimed to characterise human renal UGT activities in order to assess the contribution of glucuronidation within the kidney to the elimination of aglycones, in addition to the excretion of conjugates formed by other tissues. Studies have shown that the kidney can significantly influence the overall glucuronidation of certain compounds e.g. diphenylacetic acid, probenecid and naldixic acid 32, 33. Renal dysfunction

Acknowledgements

This study was supported by grants from The Wellcome Trust. K. A. McGurk held a Wellcome Toxicology Prize Studentship.

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    1

    The nomenclature used in this manuscript is based on published recommendations and is to be defined by the position of the variable exon within the gene complex [45]. The position of the specific isoform formerly known as HlugP4 or UGT1∗02 has yet to be resolved. As such, the nomenclature for this isoform will be stated as UGT1A8/9.

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