Abstract
UDP-glucuronosyltransferase (UGT) 2B9, isolated from a cynomolgus monkey liver cDNA library, is 89% identical to human UGT2B7 in primary amino acid sequence, and the two expressed enzymes were previously shown to catalyze the glucuronidation of many common endogenous substrates. The purpose of the present study was to characterize the reactivity of expressed UGT2B9 with important therapeutic agents and other xenobiotics. UGT2B9, stably expressed in human embryonic kidney 293 cells, catalyzes the 3-O- and 6-O-glucuronidation of morphine and the 6-O-glucuronidation of codeine. A number of other morphinan (e.g. naloxone, naltrexone, and nalorphine) and oripavine (e.g. buprenorphine) derivatives are substrates for this enzyme. In general, morphinan derivatives are glucuronidated at higher rates, compared with oripavines; however, glucuronidation efficiency values (Vmax/KM ) for the compounds are similar. Stably expressed UGT2B9 also catalyzes the glucuronidation of profen nonsteroidal anti-inflammatory drugs, fibrate hypolipidemic agents, and straight-chain fatty acids at the carboxylic acid moiety. Monoterpenoid alcohols and propanolol are glucuronidated at aliphatic hydroxyl positions. Expressed UGT2B9 exhibits enantioselective glucuronidation for (R/S)-ibuprofen, (R/S)-propanolol, and (+)/(−)-menthol. The data suggest that monkey UGT2B9 and human UGT2B7 are functionally similar.
Footnotes
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Send reprint requests to: Dr. Thomas R. Tephly, Department of Pharmacology, 2–452 Bowen Science Building, The University of Iowa, Iowa City, IA 52242.
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This work was supported by National Institutes of Health Grant GM26221 (T.R.T.), the Medical Research Council of Canada, Fonds de la Recherche en Santé du Québec (950031–103) (D.W.H.), and Endoresearch.
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↵2 In a previously published abstract (22), this transferase was referred to as UGT2B18; however, the UGT Nomenclature Committee has since revised some of the UGT nomenclature and has designated this monkey transferase as UGT2B9.
- Abbreviations used are::
- UGT
- UDP-glucuronosyltransferase
- HK293 cells
- human embryonic kidney 293 cells
- NSAIDs
- nonsteroidal anti-inflammatory drugs
- Received June 19, 1997.
- Accepted August 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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