Activation of Morphine Glucuronidation by Fatty Acyl-CoAs and Its Plasticity: A Comparative Study in Humans and Rodents Including Chimeric Mice Carrying Human Liver

• NURROCHMAD Arief

  Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University

• ISHII Yuji

  Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University

• NAKANOH Hitomi

  Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University

• INOUE Tae

  PhoenixBio. Co., Ltd.

• HORIE Toru

  PhoenixBio. Co., Ltd.

• SUGIHARA Kazumi

  Graduate School of Biomedical Sciences, Hiroshima University

• OHTA Shigeru

  Graduate School of Biomedical Sciences, Hiroshima University

• TAKETOMI Akinobu

  Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University

• MAEHARA Yoshihiko

  Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University

• YAMADA Hideyuki

  Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University

抄録

  The formation of morphine-3-glucuronide (M-3-G, pharmacologically inactive) and morphine-6-glucuronide (M-6-G, active metabolite) by liver microsomes from humans and rodents, including chimeric mice carrying human liver, was evaluated in the presence of fatty acyl-CoAs. Medium- to long-chain fatty acyl-CoAs, including oleoyl-CoAs, at a physiologic level (around 15 μM) markedly enhanced M-3-G formation catalyzed by rat liver microsomes. A separate experiment indicated that 15 μM oleoyl-CoA enhanced ¹⁴C-UDP-glucuronic acid (UDPGA) uptake by microsomes. The activation by acyl-CoAs disappeared or was greatly reduced by either pre-treating microsomes with detergent or freezing/thawing the rat liver before preparation. Many of the microsomes prepared from frozen human livers (N=14) resisted oleoyl-CoA-mediated activation of UDP-glucuronosyltransferase (UGT) activity, including M-6-G formation, which is highly specific to humans. In sharp contrast, the activity of M-6-G and M-3-G formation in freshly-prepared hepatic microsomes from chimeric mice with humanized liver was potently activated by oleoyl-CoA. Thus, acyl-CoAs activate morphine glucuronidation mediated by human as well as rat UGTs. This activation is assumed to be due to the acyl-CoA-facilitated transportation of UDPGA, and microsomes need to maintain the intact conditions required for the activation. The function of UGT appears to be dynamically changed depending on the cellular acyl-CoA level in many species.<br>

収録刊行物

• Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ

  Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 25 (3), 262-273, 2010

  日本薬物動態学会

キーワード

• UDP-glucuronosyltransferase
• activation
• chimeric mice
• fatty acyl-CoA
• human liver
• morphine

詳細情報

• CRID: 1390282680157149056
• NII論文ID: 10027582853
• NII書誌ID: AA1162652X
• DOI: 10.2133/dmpk.25.262
• ISSN: 18800920
• ISSN: 13474367
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715300306?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715300306?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2011064678
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可