Abstract
Significant evidence exists regarding altered CYP450 enzymes in chronic renal insufficiency (CRI), although none exists for the phase II enzymes. The objective of this study was to investigate the effect of CRI on hepatic and renal UDP-glucuronyltransferase (UGT) enzymes. Three groups of rats were included: CRI induced by the 5/6th nephrectomy model, control, and control pair-fed (CPF) rats. UGT activities were determined in liver and kidney microsomes by the 3- and 17-glucuronidation of β-estradiol (E2-3G and E2-17G), glucuronidation of 4-methylumbelliferone (4-MUG), and 3-glucuronidation of morphine (M3G). UGT isoforms responsible for these catalytic activities were screened using recombinant rat UGT1A1, UGT1A2, UGT1A3, UGT1A7, UGT2B2, UGT2B3, and UGT2B8. UGT protein levels were examined by Western blot analysis using polyclonal antibodies. There was no significant difference between CRI and CPF rats in hepatic and/or renal E2-3G (UGT1A1), E2-17G (UGT2B3), 4-MUG (UGT1A6), and M3G (UGT2B1) formation. Formation of E2-17G and 4-MUG in the liver and E2-3G and 4-MUG in the kidney was significantly reduced (p < 0.05) in CPF and CRI rats compared with control rats. The down-regulated glucuronidation activities were accompanied by corresponding reductions in protein content of specific UGT isoforms. These results suggest that CRI does not seem to influence the protein levels or catalytic activity of most of the major hepatic or renal UGT enzymes. The observed down-regulation of hepatic and renal UGTs in CRI and CPF rats could be caused by restricted food intake in these groups of rats.
Footnotes
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This work was supported by The Thomas F. and Kate Miller Jeffress Memorial Trust.
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The dissertation Effect of Chronic Renal Insufficiency on Drug Metabolism in Rats was submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University by Chuanhui Yu (2004).
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This article was presented in Abstract form [(2004) Effect of chronic renal failure on UDP-glucuronyltransferase enzymes in liver and kidney. American Society for Clinical Pharmacology and Therapeutics Annual Conference; 2004 March; Miami, FL].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.006601.
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ABBREVIATIONS: UGT, UDP-glucuronyltransferase; ER, endoplasmic reticulum; CRI, chronic renal insufficiency; AUC, area under the curve; 4-MU, 4-methylumbelliferone; UDPGA, UDP-glucuronic acid; HPLC, high-performance liquid chromatography; CPF, control pair-fed; E2-3G, β-estradiol 3-glucuronide; E2-17G, β-estradiol 17-glucuronide; ODS, octadecylsilane; 4-MUG, 4-methylumbelliferone glucuronide; M3G, morphine 3-glucuronide; LOD, limit of detection; LOQ, limit of quantification.
- Received July 17, 2005.
- Accepted January 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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