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Activity and Expression of Various Isoforms of Uridine Diphosphate Glucuronosyltransferase are Differentially Regulated During Hepatic Regeneration in Rats

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Purpose

Glucuronidation pathway is very important in the detoxification of endogenous and exogenous compounds. The objective of this study was to evaluate the activity and expression of various hepatic uridine diphosphate glucuronosyltransferases (UGTs) in rats at various time points after initiation of hepatic regeneration by partial hepatectomy (PHx).

Methods

The mRNA expression of various UGTs was evaluated using real-time polymerase chain reaction (real-time PCR) with specific primers. The in vitro activity of UGTs was evaluated using different substrates such as estradiol (UGT1A1), acetaminophen (UGT1A6/7), morphine (UGT2B1), testosterone (UGT2B1/3/6), androsterone (UGT2B2), and (−)-borneol (UGT2B12).

Results

Whereas the activity and mRNA expression of UGT1A1, UGT2B1, UGT2B1/3/6, UGT2B2, and UGT2B12 were lower, the activity and mRNA expression of UGT1A6/7 were preserved during hepatic regeneration. The mRNA expression of UGT2B8 was down-regulated, whereas the mRNA expression of UGT1A5 and UGT1A8 was not altered by PHx. The mRNA expression of UGT1A2 and UGT1A3 was increased during hepatic regeneration.

Conclusion

UGT-mediated drug-metabolizing ability of the liver was altered differentially in the regenerating rat liver. Individualized dosing regimen for different UGT substrates may be needed when using such substrates of these enzymes in patients with a regenerating liver, especially during the early postoperative period. However, the glucuronide conjugating capacity of the liver in the donor of a living donor liver transplantation is expected to completely return to normal with time after surgery.

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Abbreviations

Beta-2-m :

beta-2-microglobulin

GAPDH:

glyceraldehyde-3-phosphate-dehydrogenase

HPLC:

high-performance liquid chromatography

IL-6:

interleukin-6

LDLT:

living donor liver transplantation

PCR:

polymerase chain reaction

PHx:

partial hepatectomy

TNF-α:

tumor necrosis factor alpha

UGT:

uridine diphosphate glucuronosyltransferase

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Acknowledgments

The authors thank Dr. Thomas Lehmann for his technical assistance in real-time PCR, Dr. Samuel Poloyac for his technical assistance in the radioactivity measurement, and Ms. Terry McKaveney for her critical reading of this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Hui Tian, Junhai Ou & Raman Venkataramanan

  2. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Stephen C. Strom & Raman Venkataramanan

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  1. Hui Tian
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  2. Junhai Ou
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  3. Stephen C. Strom
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  4. Raman Venkataramanan
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Correspondence to Raman Venkataramanan.

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Tian, H., Ou, J., Strom, S.C. et al. Activity and Expression of Various Isoforms of Uridine Diphosphate Glucuronosyltransferase are Differentially Regulated During Hepatic Regeneration in Rats. Pharm Res 22, 2007–2015 (2005). https://doi.org/10.1007/s11095-005-8111-1

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