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 mu M oleoyl-CoA, whereas 50 mu M or more oleoyl-CoA had all 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 mu M has no ability to change the permeability of the endoplasmic reticulum (ER) membrane. although perturbation of the membrane occurred with 50 mu M oleoyl-CoA. N-Ethylmalcimide and 5,5'-dithiobis(2-nitrobenzoic acid) abolished the oleoyl-CoA (15 mu M)-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. (c) 2006 Elsevier Inc. All rights reserved.