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 cationic drugs, endogenous ligands, and some anionic drugs in plasma. Hepatic synthesis and secretion of AGP are altered during acute inflammation as well as by a number of drugs. This alteration could influence the binding of drugs and its biological function. Macrolide antibiotics are widely used in the treatment of a variety of infectious diseases. The effects of macrolide antibiotics have been studied with respect to rat AGP expression in vivo. After the individual administration of six macrolides to rats, with the exception of oleandomycin, five increased AGP levels in serum. Of these five, clarithromycin (CAM) was the most potent inducer of AGP, which reached a maximum level between 3 to 7 days after administration. CAM increased the steady-state level of AGP mRNA in liver as well as protein level in serum in a dose-dependent manner. In addition, CAM increased AGP mRNA levels in primary cultured hepatocytes. In the luciferase promoter assay, CAM potentiated dexamethasone-increased promoter activity of the AGP gene, which contained the glucocorticoid response element, in cultured rat hepatocytes, although CAM 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 tumor virus (MMTV) promoter containing functional glucocorticoid response element, CAM potentiated dexamethasone-increased promoter activity. In the adrenalectomized rats, CAM did not increase AGP levels in serum. These findings suggest that CAM may cause transcriptional induction of AGP, at least in part, via a glucocorticoid-mediated mechanism.
Komori
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, 862-0973, Kumamoto, Japan.
Kai
H
H
Shimoishi
K
K
Kabu
K
K
Nonaka
A
A
Maruyama
T
T
Tamura
K
K
Otagiri
M
M
D020121:5' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000315:Adrenalectomy; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017291:Clarithromycin / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects
D020121:5' Untranslated Regions; D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D009961:Orosomucoid; D012333:RNA, Messenger; D003907:Dexamethasone; D017291:Clarithromycin