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Research ArticleArticle

Troglitazone Glucuronidation in Human Liver and Intestine Microsomes: High Catalytic Activity of UGT1A8 and UGT1A10

Yuichiro Watanabe, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition December 2002, 30 (12) 1462-1469; DOI: https://doi.org/10.1124/dmd.30.12.1462
Yuichiro Watanabe
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Miki Nakajima
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Tsuyoshi Yokoi
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Abstract

Troglitazone glucuronidation in human liver and intestine microsomes and recombinant UDP-glucuronosyltransferases (UGTs) were thoroughly characterized. All recombinant UGT isoforms in baculovirus-infected insect cells (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15) exhibited troglitazone glucuronosyltransferase activity. Especially UGT1A8 and UGT1A10, which are expressed in extrahepatic tissues such as stomach, intestine, and colon, showed high catalytic activity, followed by UGT1A1 and UGT1A9. The kinetics of the troglitazone glucuronidation in the recombinant UGT1A10 and UGT1A1 exhibited an atypical pattern of substrate inhibition when the substrate concentration was over 200 μM. With a Michaelis-Menten equation at 6 to 200 μM troglitazone, the Km value was 11.1 ± 5.8 μM and the Vmax value was 33.6 ± 3.7 pmol/min/mg protein in recombinant UGT1A10. In recombinant UGT1A1, theKm value was 58.3 ± 29.2 μM and theVmax value was 12.3 ± 2.5 pmol/min/mg protein. The kinetics of the troglitazone glucuronidation in human liver and jejunum microsomes also exhibited an atypical pattern. TheKm value was 13.5 ± 2.0 μM and theVmax value was 34.8 ± 1.2 pmol/min/mg for troglitazone glucuronidation in human liver microsomes, and theKm value was 8.1 ± 0.3 μM and theVmax was 700.9 ± 4.3 pmol/min/mg protein in human jejunum microsomes. When the intrinsic clearance was estimated with the in vitro kinetic parameter, microsomal protein content, and weight of tissue, troglitazone glucuronidation in human intestine was 3-fold higher than that in human livers. Interindividual differences in the troglitazone glucuronosyltransferase activity in liver microsomes from 13 humans were at most 2.2-fold. The troglitazone glucuronosyltransferase activity was significantly (r = 0.579, p < 0.05) correlated with the β-estradiol 3-glucuronosyltransferase activity, which is mainly catalyzed by UGT1A1. The troglitazone glucuronosyltransferase activity in pooled human liver microsomes was strongly inhibited by bilirubin (IC50 = 1.9 μM), a typical substrate of UGT1A1. These results suggested that the troglitazone glucuronidation in human liver would be mainly catalyzed by UGT1A1. Interindividual differences in the troglitazone glucuronosyltransferase activity in S-9 samples from five human intestines was 8.2-fold. The troglitazone glucuronosyltransferase activity in human jejunum microsomes was strongly inhibited by emodin (IC50 = 15.6 μM), a typical substrate of UGT1A8 and UGT1A10, rather than by bilirubin (IC50 = 154.0 μM). Therefore, it is suggested that the troglitazone glucuronidation in human intestine might be mainly catalyzed by UGT1A8 and UGT1A10.

Footnotes

  • Abbreviations used are::
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    HPLC
    high-performance liquid chromatography
    Mrp-2
    multidrug-resistant associated protein-2
    • Received July 9, 2002.
    • Accepted September 5, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (12)
Drug Metabolism and Disposition
Vol. 30, Issue 12
1 Dec 2002
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Research ArticleArticle

Troglitazone Glucuronidation in Human Liver and Intestine Microsomes: High Catalytic Activity of UGT1A8 and UGT1A10

Yuichiro Watanabe, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition December 1, 2002, 30 (12) 1462-1469; DOI: https://doi.org/10.1124/dmd.30.12.1462

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Research ArticleArticle

Troglitazone Glucuronidation in Human Liver and Intestine Microsomes: High Catalytic Activity of UGT1A8 and UGT1A10

Yuichiro Watanabe, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition December 1, 2002, 30 (12) 1462-1469; DOI: https://doi.org/10.1124/dmd.30.12.1462
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