title: Fatty acyl-CoA as an endogenous activator of UDP-glucuronosyltransferases.
abstract: 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 microM oleoyl-CoA, whereas 50 microM 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 microM has no ability to change the permeability of the endoplasmic reticulum (ER) membrane, although perturbation of the membrane occurred with 50 microM oleoyl-CoA. N-Ethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic acid) abolished the oleoyl-CoA (15 microM)-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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Okamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Ikushiro
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002592:Cetomacrogol / Q000494:pharmacology; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005033:Ethylmaleimide / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010171:Palmitoyl Coenzyme A / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013439:Sulfhydryl Reagents / Q000494:pharmacology
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D020719:Glucuronides; D013439:Sulfhydryl Reagents; C017585:oleoyl-coenzyme A; D010171:Palmitoyl Coenzyme A; D006923:Hymecromone; D002592:Cetomacrogol; D004228:Dithionitrobenzoic Acid; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D005033:Ethylmaleimide; D004229:Dithiothreitol