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

• Published in: DRUG METABOLISM AND PHARMACOKINETICS 2010-01, Vol.25 (3), p.262-273
• Main Authors: Nurrochmad, Arief, Ishii, Yuji, Nakanoh, Hitomi, Inoue, Tae, Horie, Toru, Sugihara, Kazumi, Ohta, Shigeru, Taketomi, Akinobu, Maehara, Yoshihiko, Yamada, Hideyuki
• Format: Article
• Language: English
• Subjects: activation; Acyl Coenzyme A - pharmacology; Animals; chimeric mice; Cryopreservation; fatty acyl-CoA; Female; Glucuronosyltransferase - metabolism; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - metabolism; human liver; Humans; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; morphine; Morphine - metabolism; Morphine Derivatives; Rats; Transplantation Chimera - metabolism; UDP-glucuronosyltransferase
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.25.262

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 15mM) markedly enhanced M-3-G formation catalyzed by rat liver microsomes. A separate experiment indicated that 15mM 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.