ACADSTAFF UGM
| Title | : | Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity: A comparative study in humans and rodents including chimeric mice carrying human liver |
| Author | : |
Prof. Dr. apt. Arief Nurrochmad, M.Si., M.Sc. (1) |
| Date | : | 2010 |
| Keyword | : | UDP-glucuronosyltransferase,activation,chimeric mice,fatty acyl-CoA,human liver,morphine UDP-glucuronosyltransferase,activation,chimeric mice,fatty acyl-CoA,human liver,morphine |
| 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 formation 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-CoAmediated 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 |
| Group of Knowledge | : | Farmakologi dan Farmasi Klinik |
| Original Language | : | English |
| Level | : | Internasional |
| Status | : |
Published
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| 1 |
1-s2_0-S1347436715300306-main.pdf
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