Up-regulation by clarithromycin of alpha(1)-acid glycoprotein expression in liver and primary cultured hepatocytes

alpha (1)-Acid glycoprotein (AGP) is the major transport protein for cation ic drugs, endogenous ligands, and some anionic drugs in plasma. Hepatic syn thesis and secretion of AGP are altered during acute inflammation as well a s by a number of drugs. This alteration could influence the binding of drug s and its biological function. Macrolide antibiotics are widely used in the treatment of a variety of infectious diseases. The effects of macrolide an tibiotics have been studied with respect to rat AGP expression in vivo. Aft er the individual administration of six macrolides to rats, with the except ion of oleandomycin, live increased AGP levels in serum. Of these five, cla rithromycin (CAM) was the most potent inducer of AGP, which reached a: maxi mum level between 3 to 7 days after administration. CAM increased the stead y-state level of AGP mRNA in liver as well as protein level in serum in a d ose-dependent manner. In addition, CAM increased AGP mRNA levels in primary cultured hepatocytes. In the luciferase promoter assay, CAM potentiated de xamethasone-increased promoter activity of the AGP gene, which contained th e glucocorticoid response element, in cultured rat hepatocytes, although CA M itself had no effect on its activity. The effect of CAM and dexamethasone was diminished by glucocorticoid response element deletion or mutation or by adding the antiglucocorticoid, RU486. Further, in the mouse mammary tumo r virus (MMTV) promoter containing functional glucocorticoid response eleme nt, CAM potentiated dexamethasone-increased promoter activity. In the adren alectomized rats, CAM did not increase AGP levels in serum. These findings suggest that CAM may cause transcriptional induction of AGP, at least in pa rt, via a glucocorticoid-mediated mechanism. (C) 2001 Elsevier Science Inc. All rights reserved.