Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity: A comparative study in humans and rodents including chimeric mice carrying human liver

Arief Nurrochmad, Yuji Ishii, Hitomi Nakanoh, Tae Inoue, Toru Horie, Kazumi Sugihara, Shigeru Ohta, Akinobu Taketomi, Yoshihiko Maehara, Hideyuki Yamada

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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 mM) markedly enhanced M-3-G forma-tion catalyzed by rat liver microsomes. A separate experiment indicated that 15 mM 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 as-sumed 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 de-pending on the cellular acyl-CoA level in many species.

Original languageEnglish
Pages (from-to)262-273
Number of pages12
JournalDrug metabolism and pharmacokinetics
Volume25
Issue number3
DOIs
Publication statusPublished - 2010

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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