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Research ArticleArticle

Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6

Soundararajan Krishnaswamy, Su X. Duan, Lisa L. von Moltke, David J. Greenblatt and Michael H. Court
Drug Metabolism and Disposition January 2003, 31 (1) 133-139; DOI: https://doi.org/10.1124/dmd.31.1.133
Soundararajan Krishnaswamy
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Su X. Duan
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Lisa L. von Moltke
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David J. Greenblatt
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Michael H. Court
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Abstract

Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n = 54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of 7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative human liver microsomes (n = 7) and pooled human kidney, intestinal and lung microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis-Menten kinetics. Serotonin glucuronidation activity in these human liver microsomes had widely varying Vmax values ranging from 0.62 to 51.3 nmol/min/mg of protein but very similar apparentKm values ranging from 5.2 to 8.8 mM. Pooled human kidney, intestine, and lung microsomes hadVmax values (mean ± standard error of the estimates) of 8.8 ± 0.4, 0.22 ± 0.00, and 0.03 ± 0.00 nmol/min/mg of protein (respectively) and apparentKm values of 6.5 ± 0.9, 12.4 ± 2.0, and 4.9 ± 3.3 mM (respectively). In comparison, recombinant UGT1A6 had a Vmax of 4.5 ± 0.1 nmol/min/mg of protein and an apparent Km of 5.0 ± 0.4 mM. A highly significant correlation was found between immunoreactive UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin concentration in human liver microsomes (Rs = 0.769; P < 0.001) (n = 52). In conclusion, these results indicate that serotonin is a highly selective in vitro probe substrate for human UGT1A6.

Footnotes

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    UDPGA
    UDP-glucuronic acid
    HLM
    human liver microsomes
    HPLC
    high performance liquid chromatography
    AZT
    3′-azido-2′,3′-dideoxythymidine
    Rs
    Spearman correlation coefficient
    • Received August 13, 2002.
    • Accepted October 15, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6

Soundararajan Krishnaswamy, Su X. Duan, Lisa L. von Moltke, David J. Greenblatt and Michael H. Court
Drug Metabolism and Disposition January 1, 2003, 31 (1) 133-139; DOI: https://doi.org/10.1124/dmd.31.1.133

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Research ArticleArticle

Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6

Soundararajan Krishnaswamy, Su X. Duan, Lisa L. von Moltke, David J. Greenblatt and Michael H. Court
Drug Metabolism and Disposition January 1, 2003, 31 (1) 133-139; DOI: https://doi.org/10.1124/dmd.31.1.133
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