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Research ArticleArticle

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Katriina Itäaho, Michael H. Court, Päivi Uutela, Risto Kostiainen, Anna Radominska-Pandya and Moshe Finel
Drug Metabolism and Disposition April 2009, 37 (4) 768-775; DOI: https://doi.org/10.1124/dmd.108.025692
Katriina Itäaho
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Michael H. Court
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Päivi Uutela
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Risto Kostiainen
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Anna Radominska-Pandya
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Moshe Finel
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Abstract

The purpose of this work was to identify human UDP-glucuronosyltransferases (UGTs) capable of glucuronidating dopamine. Using a sensitive liquid chromatography-tandem mass spectrometry method, we screened all 19 known human UGTs and found that only one enzyme, UGT1A10, catalyzed dopamine glucuronidation at substantial rates, yielding both dopamine-4-O-glucuronide (37.1 pmol/min/mg) and dopamine-3-O-glucuronide (32.7 pmol/min/mg). Much lower (<2 pmol/min/mg) or no dopamine glucuronidation activity was found for all other UGTs tested at 1 mM dopamine. Evaluation of the UGT1A10 expression pattern in human tissues by quantitative reverse transcription-polymerase chain reaction confirmed that it is mainly expressed in small intestine, colon, and adipose tissue, whereas only low levels were found in trachea, stomach, liver, testis, and prostate but not in brain. Dopamine glucuronidation assays using microsomes from human liver and intestine corroborated these findings because activity in intestinal microsomes was markedly higher than that in liver microsomes. Moreover, the glucuronidation regioselectivity in intestinal microsomes was similar to that of recombinant UGT1A10, and both enzyme sources exhibited sigmoidal kinetics with substrate affinity (KA) values in the range of 2 to 3 mM. Examination of four UGT1A10 mutants, F90A, F90L, F93A, and F93L, revealed lower dopamine glucuronidation in all of them, particularly in F90A and F93A. Nonetheless, the substrate affinities of the four mutants were similar to that of UGT1A10. It is interesting to note that mutant F93L exhibited regioselectivity, conjugating dopamine at the 4-hydroxyl (OH) position approximately 3 times more efficiently than at the 3-OH position. These results shed new light on the structure and function of UGT1A10 and indicate that dopamine may be a useful probe substrate for this enzyme.

Footnotes

  • This study was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grants GM61834, GM075893]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK60109]; and the Sigrid Juselius Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.025692.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; OH, hydroxyl; UDPGA, UDP-glucuronic acid; SULT, sulfotransferase; HPLC, high-performance liquid chromatography; LC, liquid chromatography; MS/MS, tandem mass spectrometry; PCR, polymerase chain reaction; HLM, human liver microsomes; HIM, human intestinal microsomes.

    • Received November 17, 2008.
    • Accepted December 29, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (4)
Drug Metabolism and Disposition
Vol. 37, Issue 4
1 Apr 2009
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Research ArticleArticle

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Katriina Itäaho, Michael H. Court, Päivi Uutela, Risto Kostiainen, Anna Radominska-Pandya and Moshe Finel
Drug Metabolism and Disposition April 1, 2009, 37 (4) 768-775; DOI: https://doi.org/10.1124/dmd.108.025692

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Research ArticleArticle

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Katriina Itäaho, Michael H. Court, Päivi Uutela, Risto Kostiainen, Anna Radominska-Pandya and Moshe Finel
Drug Metabolism and Disposition April 1, 2009, 37 (4) 768-775; DOI: https://doi.org/10.1124/dmd.108.025692
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