TY - JOUR
T1 - Fatty acyl-CoA as an endogenous activator of UDP-glucuronosyltransferases
AU - Okamura, Kazuharu
AU - Ishii, Yuji
AU - Ikushiro, Shin ichi
AU - Mackenzie, Peter I.
AU - Yamada, Hideyuki
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research (C) (Research No. 17590128, recipient Y.I.) from the Japan Society for Promotion of Science.
PY - 2006/7/14
Y1 - 2006/7/14
N2 - The acyl-CoA-dependent modulation of hepatic microsomal UDP-glucuronosyltransferase (UGT) function in rats was studied. Oleoyl- and palmitoyl-CoAs inhibited UGT activity toward 4-methylumbelliferone in the presence of Brij 58. However, acyl-CoAs enhanced UGT activity in untreated microsomes. A maximum activation of about 8-fold over the control was observed at 15 μM oleoyl-CoA, whereas 50 μM or more oleoyl-CoA had an inhibitory effect on UGT function. Medium- and long-chain acyl-CoAs also exhibited similar effects. On the basis of resistance to tryptic digestion of UGTs, oleoyl-CoA at 15 μM has no ability to change the permeability of the endoplasmic reticulum (ER) membrane, although perturbation of the membrane occurred with 50 μM oleoyl-CoA. N-Ethylmaleimide and 5,5′-dithiobis(2-nitrobenzoic acid) abolished the oleoyl-CoA (15 μM)-dependent activation of microsomal UGT. These results suggest that: (1) acyl-CoAs play a role as an endogenous activator of UGTs, and (2) a sulfhydryl group is required for the activation of UGT by physiological concentrations of acyl-CoAs.
AB - The acyl-CoA-dependent modulation of hepatic microsomal UDP-glucuronosyltransferase (UGT) function in rats was studied. Oleoyl- and palmitoyl-CoAs inhibited UGT activity toward 4-methylumbelliferone in the presence of Brij 58. However, acyl-CoAs enhanced UGT activity in untreated microsomes. A maximum activation of about 8-fold over the control was observed at 15 μM oleoyl-CoA, whereas 50 μM or more oleoyl-CoA had an inhibitory effect on UGT function. Medium- and long-chain acyl-CoAs also exhibited similar effects. On the basis of resistance to tryptic digestion of UGTs, oleoyl-CoA at 15 μM has no ability to change the permeability of the endoplasmic reticulum (ER) membrane, although perturbation of the membrane occurred with 50 μM oleoyl-CoA. N-Ethylmaleimide and 5,5′-dithiobis(2-nitrobenzoic acid) abolished the oleoyl-CoA (15 μM)-dependent activation of microsomal UGT. These results suggest that: (1) acyl-CoAs play a role as an endogenous activator of UGTs, and (2) a sulfhydryl group is required for the activation of UGT by physiological concentrations of acyl-CoAs.
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U2 - 10.1016/j.bbrc.2006.05.089
DO - 10.1016/j.bbrc.2006.05.089
M3 - Article
C2 - 16737684
AN - SCOPUS:33744510059
SN - 0006-291X
VL - 345
SP - 1649
EP - 1656
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -