FK506 (tacrolimus) increases rat α1-acid glycoprotein expression in liver and primary cultured hepatocytes

Shimoishi, Kazuki; Kai, Hirofumi; Kabu, Koki; Komori, Takafumi; Maruyama, Toru; Otagiri, Masaki

doi:10.1016/s0014-2999(01)01002-0

Cited by 5 publications

(3 citation statements)

References 19 publications

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“…Similar results were observed for progesterone (9) and mineralocorticoid (10) receptors. FK506 modulation of GR activity at endogenous genes has also been found, such as R1-acid glycoprotein expression in the rat (11) and cyclooxygenase-2 expression in human rheumatoid synovial fibroblasts (12). Although it is tempting to conclude that effects of FK506 on GR signaling occur by targeting FKBPs in GR heterocomplexes, a report by Yamamoto and coworkers suggests an unrelated mechanism in which FK506 causes inhibition of steroid hormone export from cells by targeting membrane-based P-glycoprotein exporters (13).…”

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confidence: 99%

Differential Control of Glucocorticoid Receptor Hormone-Binding Function by Tetratricopeptide Repeat (TPR) Proteins and the Immunosuppressive Ligand FK506

2005

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Many laboratories have documented the existence of tetratricopeptide repeat (TPR) proteins (also known as immunophilins) in hormone-free steroid receptor complexes. Yet, the distinct roles of these proteins in steroid receptor action are poorly understood. In this work, we have investigated the effects of four TPR proteins (FKBP52, FKBP51, Cyp40, and PP5) on hormone-binding function of glucocorticoid receptor (GR) endogenously expressed in mammalian L929 cells. As a first step, we treated L929 cells with select immunophilin ligands [FK506, rapamycin, cyclosporin A (CsA), and cyclosporin H (CsH)], which are commonly thought to increase the GR response to hormone by inhibiting membranebased steroid exporters. As expected, all four immunophilin ligands increased both the intracellular concentration of dexamethasone and GR activity at the MMTV-CAT reporter. To determine whether these ligands could target GR function independent of steroid export mechanisms, we performed GR reporter gene assays under conditions of immunophilin ligand and dexamethasone treatment that yielded equal intracellular hormone concentrations. FK506 was found to stimulate GR transactivity beyond the effect of this ligand on hormone retention. In contrast, CsA only affected the GR through upregulation of hormone retention. By Scatchard analysis, FK506 was found to increase GR hormone-binding affinity while decreasing total binding sites for hormone. This result correlated with loss of GR-associated FKBP51 and replacement with PP5. Interestingly, no GR-associated Cyp40 was found in these cells, consistent with the ability of CsA ligand to only affect GR through the hormone export mechanism. To test the role of FKBP52 independent of FK506, FKBP52 was placed under the control of a tetracycline-inducible promoter. Upregulation of FKBP52 caused an increase in both GR hormone-binding affinity and transactivity, even in the absence of FK506. These results show that immunosuppressive ligands can alter GR hormone-binding function by changing the TPR protein composition of receptor complexes and that TPR proteins exert a hierarchical effect on this GR function in the following order: FKBP52 > PP5 > FKBP51.The glucocorticoid receptor (GR) 1 is a ligand-activated transcription factor whose macromolecular structure in the absence of hormone contains heat shock protein 90 (Hsp90) and tetratricopeptide repeat (TPR) proteins. To date, four TPR proteins (FKBP52, FKBP51, Cyp40, and PP5) have been found in so-called "mature" GR complexes, i.e., GR that is competent for binding of hormone. Because Hsp90 contains only one binding site for these proteins, four distinct GR heterocomplexes have been identified on the basis of TPR protein content (reviewed in ref 1). Although such heterogeneity implies differential functions for each GR complex, very little is known about this process. In recent work by our laboratory, differential roles for FKBP52 and FKBP51 in the regulation of hormone-induced transport of GR were uncovered (2). It was found that binding of...

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confidence: 99%

Differential Control of Glucocorticoid Receptor Hormone-Binding Function by Tetratricopeptide Repeat (TPR) Proteins and the Immunosuppressive Ligand FK506

2005

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“…Although several researchers have reported induction of AGP by DEX in rats [18,9,16], our study indicated that DEX was administered to the dogs once daily for 5 days at a dose of 2.5 or 7.5 mg. One day before and 5 days after the start of DEX treatment, the plasma AGP and ALB concentrations were measured. Fu is the unbound fraction of QN.…”

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confidence: 63%

Clinical Oral Doses of Dexamethasone Decreases Intrinsic Clearance of Quinidine, A Cytochrome P450 3A Substrate in Dogs

Zhang

Kohno

Kuroha

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. We investigated the effect of dexamethasone (DEX) at clinical doses on the pharmacokinetics of quinidine (QN) in dogs. Dogs (5 healthy 1-year-old male beagles) were orally administered DEX once daily for 5 days at 2.5 or 7.5 mg/day. QN (2 mg/kg) was intravenously injected 3 weeks before and one day after the DEX treatment. The plasma concentration of QN was determined by high-performance liquid chromatography with fluorometric detection. Plasma concentrations of albumin and α 1 -acid glycoprotein (AGP) were determined by a bromocresol green method and a single immunodiffusion method, respectively. In order to calculate unbound concentrations of QN in plasma, the binding kinetics of QN in plasma was examined by an ultrafiltration method using pooled plasma from the 5 dogs when they were drug-free. Total body clearance of QN was decreased dose-dependently By the DEX treatment, although the decrease was not statistically significant. Elimination half-lives significantly increased (more than twice at 7.5 mg), and intrinsic clearance significantly decreased (about 50%). The volume of distribution increased significantly (about two-fold). Plasma levels of AGP significantly decreased, and the unbound fraction of QN in plasma significantly increased. Our results demonstrate that clinical doses of DEX significantly affect the pharmacokinetics of QN, a CYP3A substrate in dogs, by decreasing CYP3A activity and plasma AGP levels. There is a possibility that adverse drug-drug interaction occurs during DEX therapy through its effects on CYP3A activity and plasma AGP levels. KEY WORDS: canine, clearance, CYP3A, dexamethasone, quinidine.J. Vet. Med. Sci. 68(9): 903-907, 2006 Drug metabolism is one of the determinant factors of drug disposition. Alterations in drug metabolism are, therefore, a matter of primary concern for many researchers not only in human medicine, but also veterinary medicine. Although altered drug metabolism may result from several factors, enzyme inhibition has been extensively studied and recognized as the most important factor requiring a great deal of attention in the clinical state because it may lead to fetal toxicity of co-administered drugs in some cases [6].DEX is a well-established inducer of the cytochrome P450 (CYP) 3A subfamily. There are many reports that describe induction of CYP3A through in vitro [14,10] and in vivo studies [7,17,19]. However, very high doses (more than 10 times of the clinical dose) were used in most of the in vivo studies. In canine clinics, the recommended doses of DEX are 0.05-0.3 mg/kg/day for anti-inflammatory therapy and 0.5-1 mg/kg/day for acute adrenocortical collapse and immunosuppressive therapy [4]. In our previous study [21], therefore, we examined the inducing effect of DEX on CYP3A using clinical doses in dogs and rats. Although Jayyosi et al. reported that there is no significant induction of CYP3A in dogs treated with DEX (50 mg/kg for 5 days), we observed a decrease of about 70% in the maximum reaction velocities of midazolam 4-hydroxylation in...

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“…It is important to note that gene inducers of P-gp also induce AGP expression, suggesting the coordinated regulation of these gene families (Table 1) [16,64,[71][72][73][74][75][76][77][78][79][80][81][82][83]. Additionally, majority of the agents listed in Table 1 are well-known inducers of the cythochrome P-450 enzymes, especially CYP3A [84].…”

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Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

Zsila

2007

CDM

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Plasma alpha(1)-acid glycoprotein (AGP) is an important modulator of drug disposition, since it binds and transports of a vast array of pharmaceutical agents. The ABC transporter efflux pump, P-glycoprotein (P-gp), also recognizes and binds a broad range of weakly basic and uncharged xenobiotics. Its efflux activity plays a key role in pharmacokinetics of drugs, and overexpression of P-gp in malignant cells confers multidrug resistance (MDR) to anticancer agents. Comparison of ligand specificities of AGP and P-gp revealed high similarity showing that both proteins interact with the same therapeutic classes of drugs (alpha/beta-blockers, anticancer agents, Ca(2+) antagonists, antipsychotics/neuroleptics, HIV protease inhibitors etc.) as well as with additional endo- and exogenous compounds (steroids, dyes, natural substances). A wealth of examples are presented to show the potential use of drug-AGP binding data to predict drug-P-gp interactions and vice versa. In addition, structural and functional similarities between AGP and P-gp have been highlighted. Based on these data, several proposals have been made: 1) AGP and P-gp might act synergistically in protecting cells from harmful xenobiotics; 2) An extensive shared list of their ligands allows prediction of mutual binding interactions; 3) Interaction of drugs and drug candidates, both with AGP and P-gp, should be considered to optimize pharmacotherapy and to delineate the causes of drug-drug interactions; 4) Structures of known AGP binders could be exploited in searching for novel scaffolds of P-gp modulators to overcome cancer MDR and efflux-mediated resistance in microorganisms and parasites; 5) Novel fluorescent probes for studying P-gp structure and function can be pre-selected among AGP binder agents.

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FK506 (tacrolimus) increases rat α1-acid glycoprotein expression in liver and primary cultured hepatocytes

Cited by 5 publications

References 19 publications

Differential Control of Glucocorticoid Receptor Hormone-Binding Function by Tetratricopeptide Repeat (TPR) Proteins and the Immunosuppressive Ligand FK506

Differential Control of Glucocorticoid Receptor Hormone-Binding Function by Tetratricopeptide Repeat (TPR) Proteins and the Immunosuppressive Ligand FK506

Clinical Oral Doses of Dexamethasone Decreases Intrinsic Clearance of Quinidine, A Cytochrome P450 3A Substrate in Dogs

Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

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