UDP-GLUCOSE-GLYCOPROTEIN GLUCOSYLTRANSFERASE ASSOCIATES WITH ENDOPLASMIC-RETICULUM CHAPERONES AND ITS ACTIVITY IS DECREASED IN-VIVO BY THE INHALATION ANESTHETIC HALOTHANE

Halothane causes an idiosyncratic hepatitis that is thought to result, in part, from immune reactions against one or more lumenal endoplasmi c reticulum (ER) proteins that have been covalently modified by the tr ifluoroacetyl chloride metabolite of halothane. In this study, we have identified a 170 kDa protein target of halothane in the liver of rats . The 170 kDa protein was first detected when proteins in lysates of h epatocytes from halothane-treated rats were immunoprecipitated with an tisera against several resident ER proteins. This 170 kDa protein was found to be associated with other protein targets of halothane, includ ing protein disulfide isomerase, a protein disulfide isomerase isoform , a 59 kDa carboxylesterase, and 78 kDa glucose-regulated protein. Imm unoblotting with antiserum directed against the trifluoroacetylated ha pten indicated that the 170 kDa protein was trifluoroacetylated. Based upon its subcellular localization, molecular mass, N-terminal amino a cid sequence, and antigenicity, the trifluoroacetylated 170 kDa protei n was identified as UDP-glucose:glycoprotein glucosyltransferase (UGGT ), a lumenal ER protein that is thought to have a role in the folding of N-linked glycoproteins. Moreover, treatment of rats with halothane caused a 44% decrease in the activity of liver microsomal UGGT, and at least 36% of the change in the activity of the enzyme could be due to a decrease in the level of the protein. The results suggest that the function of UGGT in folding of N-linked glycoproteins may be affected by other resident ER proteins or xenobiotics such as halothane.