Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity: a comparative study in humans and rodents including chimeric mice carrying human liver.
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 microM) markedly enhanced M-3-G formation catalyzed by rat liver microsomes. A separate experiment indicated that 15 microM oleoyl-CoA enhanced (14)C-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.
Nurrochmad
Arief
A
Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
Ishii
Yuji
Y
Nakanoh
Hitomi
H
Inoue
Tae
T
Horie
Toru
T
Sugihara
Kazumi
K
Ohta
Shigeru
S
Taketomi
Akinobu
A
Maehara
Yoshihiko
Y
Yamada
Hideyuki
H
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D015925:Cryopreservation; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives; D051381:Rats; D018183:Transplantation Chimera / Q000378:metabolism
D000214:Acyl Coenzyme A; D009022:Morphine Derivatives; C017585:oleoyl-coenzyme A; C035349:morphine-6-glucuronide; D009020:Morphine; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide