Effect of <i>Luteolin</i> on 11Beta-Hydroxysteroid Dehydrogenase in Rat Liver and Kidney

Tang, Lei; Deng, Bin; Shi, Lijuan; Wei, Binghua; Ren, Bin; Fu, Xiaohua

doi:https://doi.org/10.1155/2015/834124

Evidence-Based Complementary and Alternative Medicine

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Abstract Introduction Materials and Methods Results Discussion Conclusion Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2015 | Article ID 834124 | https://doi.org/10.1155/2015/834124

Effect of Luteolin on 11Beta-Hydroxysteroid Dehydrogenase in Rat Liver and Kidney

Lei Tang,¹Bin Deng,¹Lijuan Shi,²Binghua Wei,¹Bin Ren,¹and Xiaohua Fu³

Academic Editor: Yoshiyuki Kimura

Received01 Apr 2015

Revised03 Jun 2015

Accepted11 Jun 2015

Published25 Jun 2015

Abstract

11Beta-hydroxysteroid dehydrogenase (11β-HSD) enzymes control the glucocorticoid (GC) signaling, which is essential in regulating homeostasis. Our previous study revealed that Eclipta prostrata (EP) affected the activity and expression of 11β-HSD enzymes which might improve the efficacy and reduce the adverse drug effects of glucocorticoid in patients undergoing combinational therapy. However, it is still unclear which composition of EP plays a major role and how it works. In this paper, we chose Luteolin which is one of the main ingredients of EP and evaluated its effect and metabolism in combination with prednisone. The effects of different concentrations of Luteolin extract on prednisone/prednisolone metabolism indicated the enzyme activity of 11β-HSD, so the production rate (pmol/min per mg protein) of metabolites was used to indicate enzyme activity. Furthermore, we explored the influence of Luteolin on gene and protein expressions of 11β-HSD I/II in rat liver and kidney tissue. Our results showed that oral administration of Luteolin significantly increased the gene and protein expressions of hepatic 11β-HSD I and renal 11β-HSD II, which may improve the efficacy and reduce the adverse drug effect of glucocorticoid in clinical application. A potential clinical value of Luteolin would also be indicated in combination therapy with prednisone for the treatment of nephrotic syndrome.

1. Introduction

Glucocorticoids (GCs) are essential in regulating diverse processes in the development and homeostasis in virtually all body tissues [1]. GCs, which include endogenous cortisol and synthetic drugs, regulate the biosynthesis and metabolism of sugar, fat, and protein [2]. As one of the synthetic GCs, prednisone is commonly used for the treatment of immunological diseases, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, and nephrotic syndrome [3, 4]. The activities of GCs are controlled locally and systemically by 11β-HSD enzymes [5]. For instance, 11β-HSD enzymes are responsible for the activation and inactivation of the synthetic GCs drug prednisone, which is very important in enhancing the curative effect and avoiding unwanted reactions of prednisone [6, 7].

There are two subtypes of 11β-HSD enzymes: 11β-HSD type 1 (11β-HSD I), which acts as an oxoreductase-generating enzyme predominantly activating GCs in liver; 11β-HSD type 2 (11β-HSD II), which impedes binding of GCs to the nonselective mineralocorticoid receptor (MR) in mineralocorticoid target tissues such as kidney and colon [8–10]. 11β-HSD I shows predominant activity in liver, where the preferential usage of NADPH for steroid biosynthesis is thought to convert prednisone to prednisolone [10, 11]. In contrast to the 11β-HSD I enzyme, 11β-HSD II relies solely on its oxidant cosubstrate, acting exclusively as a dehydrogenase to catalyze the conversion of prednisolone to inactive prednisone in kidney [12, 13]. Moreover, 11β-HSD II acts as a “gate-keeper” to protect MR from high concentrations of GCs [14–16]. Kidney injury can cause hypertension and hypokalemia as a consequence of impaired inactivation of cortisol (inhibition of 11β-HSD2) [15, 17].

In the previous study, we proved that Eclipta prostrata (EP) significantly affected the activity and expression of 11β-HSD enzymes, which might improve the efficacy and reduce the adverse drug effects of glucocorticoid in patients undergoing combinational therapy [18]. However, to the best of our knowledge, no further investigation has been performed to show which composition of EP plays a major role and how it works.

By analyzing the composition of many batches of commercial available EP, we found that the main constituents of EP include Luteolin, Luteolin-7-oxygen-glucosidase, Apigenin, and Apigenin-7-oxygen-glucosidase. According to the recent research, Luteolin, a flavonoid of EP, was found to potently inhibit 20α-hydroxysteroid dehydrogenase [19–21], which belonged to 11β-HSD family. Therefore, we wonder if coadministration of Luteolin could influence 11β-HSD enzymes and the clinical effects in combination with glucocorticoid.

In this paper, we chose Luteolin to evaluate its effect and metabolism in combination with prednisone. The production rate (pmol/min per mg protein) of metabolites was used to indicate enzyme activity. Furthermore, we explored the influence of Luteolin on gene and protein expressions of 11β-HSD I/II in rat liver and kidney tissue.

2. Materials and Methods

2.1. Experimental Animals

Male Sprague-Dawley rats weighed 200–250 g were purchased from the Medical Experimental Animal Center of Guangdong Province. The animals were housed at an ambient temperature of 20–25°C and relative humidity 40–70% with 12 h-light/dark cycle. They are allowed free access to the standard rodent chow and clean water.

This study was performed with the approval of the local ethical committee and all the experiments were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. 24 rats were randomly divided into 4 groups and orally administrated with vehicle (1% CMC-Na solution) or Luteolin (5 mg/kg, 10 mg/kg, or 20 mg/kg daily) for 14 days. On the next morning, the livers and kidneys of each rat were harvested as soon as possible and stored in liquid nitrogen after being washed with ice-cold 0.9% NaCl solution until usage.

2.2. Chemicals and Reagents

Luteolin (purity > 98%, batch number: XC071225) was purchased from Xi’an Xiaocao Botanical Development Co., Ltd. (Xi’an, China). Sodium carboxymethyl cellulose (CMC-Na), prednisone, prednisolone, and dexamethasone (internal standard for HPLC analysis) were purchased from Sigma-Aldrich Corporation (St. Louis, MO, USA). Methanol of HPLC grade was purchased from TEDIA Company Inc. (Beijing, China). The following items were purchased from the cited commercial sources: anti-11β-HSDI (Abcam, Cambridge, UK, dilution 1 : 800), anti-11β-HSD II (Abcam, Cambridge, UK, dilution 1 : 1000), GAPDH (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA, dilution 1 : 500) antibodies, goat anti-rabbit IgG (HþL) HRP (BS13278), GAPDH (AP0063), and goat anti-mouse IgG (HþL) HRP (BS12478). All other reagents were of analytical grade.

2.3. Development and Validation of an HPLC Method

2.3.1. Equipment and Chromatographic Conditions

The equipment employed for HPLC analysis was a Waters system (Waters, Avondale, CA) equipped with a Waters 600 quaternary pump, a Waters 2489 UV-vis detector, a Waters 717 Plus automatic injector and a Workstation (Empower). Chromatographic separation of the analytes was carried out at 40°C by using a Nucleodur 100-5 C18 (5 μm, I.D 4.6 mm × 250 mm), with a mobile phase containing a mixture of A (methanol : 0.2% phosphoric acid = 55 : 45 v/v) and B (acetonitrile). The flow-rate was 1.0 mL/min and absorbance was measured at 240 nm. The total running time was 35 min for each sample.

2.3.2. Method Validation

According to the SFDA guideline, the HPLC method was validated for the specificity of the detection method, the linearity of the calibration curve, accuracy, precision, and recovery. There was no significant interference at the expected retention times of the analytes and interior label. The analytes showed satisfactory linearity over the studied concentration ranges in rat tissues. The intra- and interbatch precision and accuracy were within recommended limits. Therefore, the validated HPLC method was applicable for detecting the concentrations of prednisone and prednisolone.

2.4. Preparation of Rat Liver and Kidney Microsomes

Rats were euthanized with diethyl ether before livers and kidneys were harvested and washed with ice-cold 0.9% NaCl solution. The weighted tissues were divided into several parts and homogenized in 2 volumes sucrose homogenization buffer after being washed with ice-cold sucrose at 4°C. The homogenate was subjected to centrifugation at 16000 g for 20 min at 4°C. The supernatant fraction was subjected to ultracentrifugation at 100000 g for 60 min at 4°C. Then the supernatant was discarded and the sediment was washed and resuspended in potassium pyrophosphate buffer and reisolated by ultracentrifugation (100000 g for 60 min at 4°C), successively. The washed microsomes were resuspended in 2 volumes of Tris-HCl buffer containing 20% of glycerol and stored at 80°C until usage.

2.5. Microsomal Incubation

In order to obtain the optimal condition of the metabolism of prednisone/prednisolone in liver and kidney, the effects of incubation time and microsome concentration on the metabolism of prednisone in rat liver and kidney microsome were investigated. The method of liver microsomes incubation system was as follows: 20 μL liver microsomes (5 μg/μL), 20 μL standard prednisone (1 mg/mL), and 140 μL potassium phosphate buffer (100 mM, pH 7.4) were incubated for 5 min at 37°C. The reaction was started by adding 20 μL of NADPH and stopped by adding 600 μL methanol after 25 min. Then 10 μL dexamethasone (10 mg/mL, internal standard) and 600 μL methanols were added to 200 μL of the above mixture, vortexed for 1 min, and centrifuged at 10800 rpm for 5 min. The supernatant fraction was obtained and 10 μL of which was injected into HPLC system for analysis. The production rate (pmol/mg protein/min) of metabolites was used to evaluate the enzyme activity.

The method of kidney microsomes incubation system was the same as that of liver except for the concentration of microsomes (3 μg/μL), the promoter agent (NADP+), and the reaction time (45 min).

2.6. RT-qPCR

For mRNA quantification, total RNA was extracted with ice-cold Trizol reagent (Sigma) and then reverse-transcribed to complementary DNA (cDNA) using Prime script RT reagent kit according to the manufacturer’s protocol. Equal amounts of cDNA were used in real-time quantitative polymerase chain reaction (RT-qPCR). All the PCR reactions were carried out using SYBR Premix Ex TaqTM kit (Takara, Kyoto, Japan) and followed manufacturer’s instructions. The 11β-HSD I and 11β-HSD II expression were measured by fluorescence quantitative RT-qPCR method. The β-actin gene was used as an internal control for normalization in parallel with each gene examined. The values obtained for the target gene expression were normalized to β-actin and quantified relative to the expression in control samples. The cDNA synthesis conditions were 37°C 15 min for reverse transcription reaction and 85°C 5 s for inactivation of the reverse transcription enzyme, then cooled to room temperature, and stored at −20°C. Amplification was performed with the Light Cycler 2.0 Real-Time Detection System (Roche, Hercules, CA, USA) using the following protocol: 40 cycles (5 s at 95°C and 34 s at 60°C) after an initial activation step for 30 s at 95°C. Primer sequences were shown in Table 1.

2.7. Western Blot

The Western blot was carried out to measure the expression of 11β-HSD I and 11β-HSD II in liver and kidney. Livers and kidneys were excised immediately after the rats were euthanized. Approximately 100 mg of tissues was homogenized in 1 mL of RIPA buffer and 10 μL of phenylmethylsulfonyl fluoride (PMSF). Total protein was extracted by centrifugation at 15000 rpm for 30 min at 4°C and quantified by enhanced bicinchoninic acid (BCA) protein assay kit. An equal amount of protein was resolved by 10% SDS-PAGE and transferred electrophoretically to polyvinylidene difluoride microporous membranes (Millipore, Bedford, MA, USA). The membranes were blocked with 5% skim milk or BSA in TBST buffer (20 mM Tris-HCl, pH 7.6, 140 mM NaCl, and 0.1% Tween-20) for 2 h at 25°C and then subsequently incubated with primary and secondary antibodies. The antibody reactivity was detected by ECL and then quantified by densitometry with ImageJ 1.44p software.

2.8. Statistical Analysis

Statistical analyses were performed using SPSS 17.0 statistical software (SPSS Inc., Chicago, USA) statistical software. Results were expressed as the mean ± SD. Student’s -test was performed for statistical comparison of the results of enzyme, and the criterion of significance was set at . Using one-way analysis of variance (ANOVA), the differences among groups of gene and protein expression were evaluated and considered statistically significant when .

3. Results

3.1. Effects of Luteolin on Enzyme Activity of 11β-HSD I and 11β-HSD II in Rat Liver and Kidney

Effects of Luteolin on enzyme activity of 11β-HSD I/II in rat liver and kidney were shown in Figure 1. Compared with the negative control group, the 11β-HSD I activities from all orally administrated Luteolin groups were increased with the medium and high dose groups exhibiting significantly statistical differences (). The activities of renal 11β-HSD II from all treatment groups were significantly increased compared to the negative control group. The relative 11β-HSD II activities of low, medium, and high dose groups were %, %, and %, respectively. There were significant differences () between treatment groups and the negative control group. Therefore, Luteolin could significantly induce the activity of hepatic 11β-HSD I and renal 11β-HSD II, and the effects were positively related to concentration of Luteolin. The effects of Luteolin on rat liver/kidney 11β-HSD indicated that Luteolin could affect the metabolism of prednisone/prednisolone and regulate the local tissue concentrations by 11β-HSD modulation.

(a) Liver

(b) Kidney

3.2. Effects of Luteolin on Gene Expression of 11β-HSD I and 11β-HSD II in Rat Liver and Kidney

Figure 2 showed the relative gene expressions of 11β-HSD I/II in rat liver and kidney after orally administration of vehicle (1% CMC-Na solution) or Luteolin at the dosages of 5 mg/kg, 10 mg/kg, or 20 mg/kg daily for 14 days. Compared with the control group, treatment of Luteolin (5, 10, and 20 mg/kg) significantly increased hepatic 11β-HSD I gene expression by 29%, 20%, and 70%, respectively, whereas those of hepatic 11β-HSD II gene expressions were decreased by 45%, 41%, and 70%, respectively. It was found that Luteolin significantly decreased the gene expression level of 11β-HSD I () and upregulated that of 11β-HSD II () in kidney. Therefore, Luteolin significantly induced gene expression of hepatic 11β-HSD I and renal 11β-HSD II, whereas inhibited the gene expression of hepatic 11β-HSD II and renal 11β-HSD I.

(a) Liver

(b) Kidney

3.3. Effects of Luteolin on Protein Expression of 11β-HSD I and 11β-HSD II in Rat Liver and Kidney

As shown in Figure 3, the relative protein expression levels of 11β-HSD I/II in rat liver and kidney were investigated by western blot analysis. Compared with control group, the protein expressions of 11β-HSD I in rat liver treated with Luteolin (5, 10, and 20 mg/kg) were increased by 26%, 49%, and 66%, respectively (Figure 3(a)), whereas the protein expressions of 11β-HSD II were reduced by 24%, 34%, and 56%, respectively (Figure 3(b)). In contrast, the protein expressions of 11β-HSD II in rat kidney treated with Luteolin (5, 10, and 20 mg/kg) were increased by 47%, 55%, and 84%, respectively, while those of 11β-HSD I were decreased by 32%, 37%, and 47%, respectively (Figures 3(c) and 3(d)). The influence of Luteolin on protein expression of 11β-HSD showed dose-dependent relationship, and high-dose group had the most significant effect. Therefore, Luteolin upregulated the protein expression of 11β-HSD I and downregulated the protein expression of 11β-HSD II in liver. The effects of Luteolin on the protein expression of 11β-HSD II and 11β-HSD I in kidney were opposite compared with those in liver.

(a) Liver

(b) Liver

(c) Kidney

(d) Kidney

Figure 3

Effects of Luteolin on the protein expression of 11β-HSD I and 11β-HSD II in rat liver (a and b) and kidney (c and d). Rats were orally administrated with vehicle (CMC-Na) or Luteolin (5 mg/kg, 10 mg/kg, or 20 mg/kg) for 14 days. Liver and kidney were harvested and then 11β-HSD I and 11β-HSD II protein levels were analyzed. Data are expressed as fold change over the control group (mean ± SD, ) , . 1, 2: control group; 3, 4: Luteolin 5 mg/kg; 5, 6: Luteolin 10 mg/kg; 7, 8: Luteolin 20 mg/kg.

4. Discussion

In recent studies, a lot of parameters were calculated to represent the enzyme activity of 11β-HSD, including measuring the AUC ratio of prednisone/prednisolone in plasma [22–24] and ratio of (THF+5α-THF)/THE [15, 25, 26] (THB+5α-THB)/THA [27] (THF: tetrahydrocortisol, 5α-THF: 5alpha-tetrahydrocortisol, THE: tetrahydrocortisone, THB: tetrahydrocorticosterone, 5α-THB: 5alpha-tetrahydrocorticosterone, and THA: 11-dehydro-tetrahydrocorticosterone). Furthermore, 11β-HSD activities could also be detected by microsomal incubation with radiolabeled 3H-corticosterone [28, 29] and 3H-cortisone [30] as substrate. The purpose of this study was to examine the effect of drug combination with Luteolin on metabolism of prednisone/prednisolone through 11β-HSD in liver and kidney. Therefore, prednisone and prednisolone were used as the substrates to estimate the enzyme activity of 11β-HSD I/II in the microsomal incubation.

To ensure the accuracy of enzyme activity, the concentration of substrate must exceed enzyme catalysis capacity. Thus, 100 μg/mL prednisone/prednisolone was used which fully met the requirements. Through the comparison and analysis of dissolving in 1%, 3%, 5%, 7%, 10%, 15%, and 20% methyl alcohol, the substrates were dissolved in 10% methyl alcohol because of good solubility.

It has been confirmed that activation of prednisone in patients and animal models improved the nephrotic syndrome; thus prednisolone plasma concentration was lower than normal, which would affect the efficacy of hormone. Meanwhile the activity of 11β-HSD II in kidney decreased and could not effectively inactivate glucocorticoids, which would cause water-sodium retention, hypertension, and other mineral corticoid-like adverse reactions. Luteolin can induce activity of 11β-HSD I in liver, which in turn promote the metabolic activation of prednisone, increase the prednisolone plasma concentration, and improve hormone efficacy. Furthermore, Luteolin can accelerate the inactivation of prednisolone in kidney by inducing renal 11β-HSD II and thus can weaken the mineralocorticoid hormone-like prednisolone-induced adverse reactions caused by prednisolone. Therefore, the combination of Luteolin and prednisone in the treatment of kidney disease could accelerate the inactivation of prednisolone and reduce the adverse effects of hormones. The effect of Luteolin on 11β-HSD activities in rat liver/kidney microsomes was similar to that of EP, indicating a potential clinical value of Luteolin in combination with prednisone for the treatment of nephrotic syndrome.

As shown in Figure 3(a), Luteolin induced the gene expression of 11β-HSD I and inhibited the gene expression of 11β-HSD II in liver. While in Figure 3(b), the gene expression of 11β-HSD I was restrained. In contrast, the gene expression of 11β-HSD II was induced. It indicates that Luteolin can promote the activation and metabolism of prednisone in liver by inducing the gene expression of 11β-HSD I. Meanwhile, the upregulated gene expression of 11β-HSD II can accelerate the inactivation of prednisolone in kidney and reduced the adverse effects.

Compared with the control group, continuous administration of Luteolin for 14 days significantly upregulated protein expressions of 11β-HSD I and downregulated levels of 11β-HSD II in liver, while Luteolin downregulated the expression of 11β-HSD I and upregulated the expression of 11β-HSD II in kidney. The effect of Luteolin on 11β-HSD protein was concentration-dependent, and high-dose group had the most significant effect. The results of RT-qPCR, western blot, and in vitro activity showed that Luteolin could affect the interconversion between prednisolone and prednisone by inducing mRNA and protein expression of hepatic 11β-HSD I and renal 11β-HSD II. The results suggest that the drug interactions between Luteolin and glucocorticoids should be paid attention to, which will provide a theoretical basis for clinical combination therapy.

The content of Luteolin in EP was 0.45 mg/g, determined by HPLC. The content of Luteolin was significantly higher than the other flavonoids. In the previous research, oral administration of EP significantly increased the activity and expression of 11β-HSD I in the liver and 11β-HSD II in the kidney which was similar with Luteolin. Therefore, conclusion could be drawn that Luteolin is one of the constituents that is responsible for the clinical effects of EP.

5. Conclusion

In summary, oral administration of Luteolin significantly increased the gene and protein expression of hepatic 11β-HSD I and renal 11β-HSD II, which may improve the efficacy and reduces the adverse drug effects of glucocorticoid in clinical application. Our study addressed a potential clinical value of Luteolin in combination with prednisone in the treatment of nephrotic syndrome.

Conflict of Interests

The authors have declared no conflict of interests.

Authors’ Contribution

Lei Tang, Bin Deng, and Lijuan Shi have equal contribution to this work. They are all the first authors.

Acknowledgments

The authors thank the Science and Information Technology of Guangzhou and Hospital Pharmacy Foundation of Guangdong Pharmaceutical Association (2013A25) for financial support of this study.

References

R. W. Hunter and M. A. Bailey, “Glucocorticoids and 11 $β$ -hydroxysteroid dehydrogenases: mechanisms for hypertension,” Current Opinion in Pharmacology, vol. 21, pp. 105–114, 2015.
View at: Publisher Site | Google Scholar
J. Q. Rose, A. M. Yurchak, and W. J. Jusko, “Dose dependent pharmacokinetics of prednisone and prednisolone in man,” Journal of Pharmacokinetics and Biopharmaceutics, vol. 9, no. 4, pp. 389–417, 1981.
View at: Google Scholar
M. Conti, F. J. Frey, G. Escher, C. Marone, and B. M. Frey, “Renal handling of prednisolone/prednisone: effect of steroid dose and 11β-hydroxysteroid dehydrogenase,” Nephrology Dialysis Transplantation, vol. 9, no. 11, pp. 1622–1628, 1994.
View at: Google Scholar
M. E. Pickup, “Clinical pharmacokinetics of prednisone and prednisolone,” Clinical Pharmacokinetics, vol. 4, no. 2, pp. 111–128, 1979.
View at: Publisher Site | Google Scholar
P. Ferrari, “The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1802, no. 12, pp. 1178–1187, 2010.
View at: Publisher Site | Google Scholar
P. M. Stewart and Z. S. Krozowski, “11β-hydroxysteroid dehydrogenase,” Vitamins and Hormones, vol. 57, pp. 249–324, 1999.
View at: Publisher Site | Google Scholar
M. Quinkler, W. Oelkers, and S. Diederich, “Clinical implications of glucocorticoid metabolism by 11β-hydroxysteroid dehydrogenases in target tissues,” European Journal of Endocrinology, vol. 144, no. 2, pp. 87–97, 2001.
View at: Publisher Site | Google Scholar
Z. Krozowski, K. X. Z. Li, K. Koyama et al., “The type I and type II 11β-hydroxysteroid dehydrogenase enzymes,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 69, no. 1–6, pp. 391–401, 1999.
View at: Publisher Site | Google Scholar
A. N. Amweg, N. R. Salvetti, M. L. Stangaferro et al., “Ovarian localization of 11β-hydroxysteroid dehydrogenase (11βHSD): effects of ACTH stimulation and its relationship with bovine cystic ovarian disease,” Domestic Animal Endocrinology, vol. 45, no. 3, pp. 126–140, 2013.
View at: Publisher Site | Google Scholar
C. A. Staab and E. Maser, “11β-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation,” Journal of Steroid Biochemistry and Molecular Biology, vol. 119, no. 1-2, pp. 56–72, 2010.
View at: Publisher Site | Google Scholar
A. Odermatt and L. G. Nashev, “The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: physiological and toxicological considerations,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 119, no. 1-2, pp. 1–13, 2010.
View at: Publisher Site | Google Scholar
V. Sharp, L. M. Thurston, R. C. Fowkes, and A. E. Michael, “Expression and activities of 11βHSD enzymes in the testes and reproductive tracts of sexually immature male pigs,” Journal of Steroid Biochemistry and Molecular Biology, vol. 115, no. 3–5, pp. 98–106, 2009.
View at: Publisher Site | Google Scholar
R.-S. Ge, Q. Dong, E.-M. Niu et al., “11β-hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate,” Endocrinology, vol. 146, no. 6, pp. 2657–2664, 2005.
View at: Publisher Site | Google Scholar
A. Odermatt and D. V. Kratschmar, “Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: an overview,” Molecular and Cellular Endocrinology, vol. 350, no. 2, pp. 168–186, 2012.
View at: Publisher Site | Google Scholar
J. W. Tomlinson, M. Sherlock, B. Hughes et al., “Inhibition of 11β-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 3, pp. 857–864, 2007.
View at: Publisher Site | Google Scholar
P. Ferrari, “The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension,” Biochimica et Biophysica Acta, vol. 1802, no. 12, pp. 1178–1187, 2010.
View at: Publisher Site | Google Scholar
M. Lacey, J. Bohday, S. M. R. Fonseka, A. I. Ullah, and S. A. Whitehead, “Dose-response effects of phytoestrogens on the activity and expression of 3β-hydroxysteroid dehydrogenase and aromatase in human granulosa-luteal cells,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 96, no. 3-4, pp. 279–286, 2005.
View at: Publisher Site | Google Scholar
C. Xu, B. Wei, X. Fu et al., “Effect of Eclipta prostrata on 11beta-hydroxysteroid dehydrogenase in rat liver and kidney,” Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 651053, 9 pages, 2014.
View at: Publisher Site | Google Scholar
K. Ugocsai, A. Varga, P. Molnár, S. Antus, and J. Molnár, “Effects of selected flavonoids and carotenoids on drug accumulation and apoptosis induction in multidrug-resistant colon cancer cells expressing MDR1/LRP,” In Vivo, vol. 19, no. 2, pp. 433–438, 2005.
View at: Google Scholar
J. Chen, H. Lin, and M. Hu, “Metabolism of flavonoids via enteric recycling: role of intestinal disposition,” Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 3, pp. 1228–1235, 2003.
View at: Publisher Site | Google Scholar
H. Shimada, K. Miura, and Y. Imamura, “Characteristics and inhibition by flavonoids of 20α-hydroxysteroid dehydrogenase activity in mouse tissues,” Life Sciences, vol. 78, no. 25, pp. 2931–2936, 2006.
View at: Publisher Site | Google Scholar
R. Courtney, P. M. Stewart, M. Toh, M.-N. Ndongo, R. A. Calle, and B. Hirshberg, “Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 2, pp. 550–556, 2008.
View at: Publisher Site | Google Scholar
B. Vogt, B. Dick, H.-P. Marti, F. J. Frey, and B. M. Frey, “Reduced 11β-hydroxysteroid dehydrogenase activity in experimental nephrotic syndrome,” Nephrology Dialysis Transplantation, vol. 17, no. 5, pp. 753–758, 2002.
View at: Publisher Site | Google Scholar
M. Homma, A. Tanaka, K. Hino et al., “Assessing systemic 11β-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure,” Metabolism: Clinical and Experimental, vol. 50, no. 7, pp. 801–804, 2001.
View at: Publisher Site | Google Scholar
M. Quinkler, D. Zehnder, J. Lepenies et al., “Expression of renal 11β-hydroxysteroid dehydrogenase type 2 is decreased in patients with impaired renal function,” European Journal of Endocrinology, vol. 153, no. 2, pp. 291–299, 2005.
View at: Publisher Site | Google Scholar
M. N. Kerstens, H. Buter, G. J. Navis, and R. P. F. Dullaart, “11β-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade,” European Journal of Clinical Investigation, vol. 32, no. 7, pp. 513–518, 2002.
View at: Publisher Site | Google Scholar
B. Vogt, B. Dick, V. N'Gankam, F. J. Frey, and B. M. Frey, “Reduced 11β-hydroxysteroid dehydrogenase activity in patients with the nephrotic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 2, pp. 811–814, 1999.
View at: Publisher Site | Google Scholar
N. L. Yeyati, M. E. Altuna, M. C. Damasco, and M. A. M. Laughlin, “Role of 11β-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure,” Brazilian Journal of Medical and Biological Research, vol. 43, no. 1, pp. 52–56, 2010.
View at: Publisher Site | Google Scholar
P. Ergang, P. Leden, K. Vagnerová et al., “Local metabolism of glucocorticoids and its role in rat adjuvant arthritis,” Molecular and Cellular Endocrinology, vol. 323, no. 2, pp. 155–160, 2010.
View at: Publisher Site | Google Scholar
W. J. Inder, V. R. Obeyesekere, F. P. Alford, and C. Jang, “Skeletal muscle 11βHSD1 activity of nondiabetic subjects is unaltered in central obesity-associated insulin resistance,” Hormone and Metabolic Research, vol. 43, no. 4, pp. 257–260, 2011.
View at: Publisher Site | Google Scholar

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Copyright © 2015 Lei Tang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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