ATP serves as an endogenous inhibitor of UDP-glucuronosyltransferase (UGT): A new insight into the latency of UGT

Yuji Ishii, Kie An, Yoshio Nishimura, Hideyuki Yamada

研究成果: ジャーナルへの寄稿記事

15 引用 (Scopus)

抄録

We have suggested that adenine-related compounds are allosteric inhibitors of UGT in rat liver microsomes (RLM) treated with detergent. To clarify whether the same occurs with a pore-forming peptide, alamethicin, the effects of adenine-related compounds on 4-metylumbelliferone (4-MU) glucuronidation were examined using RLM and human liver microsomes (HLM). ATP inhibited 4-MU glucuronidation when polyoxyethylene cetyl alcohol ether (Brij-58)-treated RLM were used (IC50 = approximately 70 μM). However, alamethicin-treated RLM exhibited a lower susceptibility (IC50 = approximately 460 μM) than Brij-58-treated RLM. A similar phenomenon was observed when pooled HLM were used. Then, the endogenous ATP content of RLM was determined in the presence and absence of alamethicin or detergent, and although no ATP remained in the microsomal pellets after Brij-58 treatment, more than half of the microsomal ATP remained even after treatment with alamethicin. Furthermore, the Vmax in the absence of an adenine-related compound was approximately three times higher in Brij-58-treated than in alamethicin-treated RLM. The difference in the inhibitory potency observed was due to the difference in remaining endogenous ATP and the accessibility of exogenous ATP to the luminal side of the endoplasmic reticulum (ER), where the active site of UDP-glucuronosyltransferase (UGT) is located. Gefitinib (Iressa), a protein tyrosine kinase inhibitor, markedly inhibited human UGT1A9 activity. It is interesting to note that AMP antagonized Gefitinib-provoked inhibition of UGT1A9, and ATP exhibited an additive inhibitory effect at a lower concentration. Therefore, Gefitinib inhibits UGT1A9 at the common ATP-binding site shared with ATP and AMP. Releasing adenine nucleotide from the ER is suggested to be one of the mechanisms that explain the "latency" of UGT.

元の言語英語
ページ(範囲)2081-2089
ページ数9
ジャーナルDrug Metabolism and Disposition
40
発行部数11
DOI
出版物ステータス出版済み - 11 1 2012

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Glucuronosyltransferase
Liver Microsomes
Alamethicin
Adenosine Triphosphate
Cetomacrogol
Adenine
Adenosine Monophosphate
Endoplasmic Reticulum
Detergents
Inhibitory Concentration 50
Adenine Nucleotides
Protein Kinase Inhibitors
Human Activities
Ether
Protein-Tyrosine Kinases
Catalytic Domain
Binding Sites
Peptides
gefitinib

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

これを引用

ATP serves as an endogenous inhibitor of UDP-glucuronosyltransferase (UGT) : A new insight into the latency of UGT. / Ishii, Yuji; An, Kie; Nishimura, Yoshio; Yamada, Hideyuki.

:: Drug Metabolism and Disposition, 巻 40, 番号 11, 01.11.2012, p. 2081-2089.

研究成果: ジャーナルへの寄稿記事

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