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

作者：Nurrochmad Arief; Ishii Yuji^*; Nakanoh Hitomi; Inoue Tae; Horie Toru; Sugihara Kazumi; Ohta Shigeru; Taketomi Akinobu; Maehara Yoshihiko; Yamada Hideyuki

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

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

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 formation catalyzed by rat liver microsomes. A separate experiment indicated that 15 mM oleoyl-CoA enhanced C-14-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.

• 出版日期2010