To the Editor:
We read with interest an article by Zhao et al. entitled “Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro” recently published in Fertility and Sterility (1). The authors showed that synthetic glucocorticoid dexamethasone-induced insulin resistance in theca cells is diminished by berberine.
We speculate here that the effects of berberine described by Zhao et al. could be explained by berberine interactions with aryl hydrocarbon receptor (AhR) and consequently could involve a cross-talk between AhR and glucocorticoid receptor (GR). Following facts favor our hypothesis:
(i) Biological effects of dexamethasone occur primarily through GR by transcriptional regulation of various genes. It was demonstrated that berberine has no effect on the expression and transcriptional activity of human GR (2). Therefore, berberine effects on dexamethasone-induced insulin resistance probably do not involve direct interaction between berberine and GR.
(ii) Berberine is an activator of AhR, and it induces expression of AhR-dependent genes such as CYP1A1 in human and rat cells (3).
(iii) A mutual interactions between AhR and GR were described in HepG2 and HeLa human cancer cell lines (4, 5) and in human hepatocytes (6, 7). It was reported that AhR activation by compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin influences the expression and activity of GR and vice versa, activation of GR by dexamethasone alters the expression and functions of AhR (4, 5).
Overall, we hypothesize that diminution of dexamethasone-induced insulin resistance by berberine could be due to the activation of AhR by berberine and consequent interaction between AhR- and GR-signaling.
Zdenek Dvorak, Ph.D.
Radim Vrzal, Ph.D.
Department of Cell Biology and Genetics
Faculty of Science
Olomouc, Czech Republic
1. Zhao L, Li W, Han F, Hou L, Baillargeon JP, Kuang H, Wang Y and Wu X, Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro. Fertil Steril.
2. Dvorak Z, Vrzal R, Maurel P and Ulrichova J, Differential effects of selected natural compounds with anti-inflammatory activity on the glucocorticoid receptor and NF-kappaB in HeLa cells. Chem Biol Interact 159(2): 117-28, 2006.
3. Vrzal R, Zdarilova A, Ulrichova J, Blaha L, Giesy JP and Dvorak Z, Activation of the aryl hydrocarbon receptor by berberine in HepG2 and H4IIE cells: Biphasic effect on CYP1A1. Biochem Pharmacol 70(6): 925-36, 2005.
4. Dvorak Z, Vrzal R, Pavek P and Ulrichova J, An evidence for regulatory cross-talk between aryl hydrocarbon receptor and glucocorticoid receptor in HepG2 cells. Physiol Res 57(3): 427-35, 2008.
5. Vrzal R, Ulrichova J, Dvorak Z and Pavek P, Glucocorticoid receptor functions in HeLa cells are perturbed by 2,3,8,9-tetrachlorodibenzo-p-dioxin (TCDD). Drug Metab Lett 1(4): 311-314, 2007.
6. Vrzal R, Daujat-Chavanieu M, Pascussi JM, Ulrichova J, Maurel P and Dvorak Z, Microtubules-interfering agents restrict aryl hydrocarbon receptor-mediated CYP1A2 induction in primary cultures of human hepatocytes via c-jun-N-terminal kinase and glucocorticoid receptor. Eur J Pharmacol 581(3): 244-54, 2008.
7. Vrzal R, Stejskalova L, Monostory K, Maurel P, Bachleda P, Pavek P and Dvorak Z, Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact 179(2-3): 288-96, 2009.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.11.014
The Authors Respond:
We appreciate the important points made by Zdenek Dvorak and Radim Vrzal in their Letter to the Editor.
Berberine is used to moderate glucose and lipid metabolism in clinic (1). In our study, berberine has been shown to diminish insulin resistance (IR) and androgenic potentials in theca cells induced by dexamethasone (DEX) (2). Current data indicate that aryl hydrocarbon receptor (AhR), which can be activated by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), plays important roles in ovarian function. The potential antagonistic roles of AhR on glucocorticoid receptor (GR) lying in reproductive and metabolic process may explain the mechanism of berberine reduceing IR.
In studies of the mechanism of polycystic ovary syndrome (PCOS), IR has a pivotal role in the pathogenesis of ovarian androgen excess. IR exists within PCOS ovaries and is caused by defective insulin pathways (3). In clinic, DEX can induce metabolic changes such as Cushing’s syndrome and IR(4), and berberine is used to remedy type 2 diabetes and IR (5). DEX induces IR via GR in rat adipocytes, and its effect can be attenuated by glucocorticoid receptor antagonist RU 38486 (6). Berberine achieves its function through multipathways (7) and possibly by AhR (8). TCDD can increase insulin-like growth factor binding protein-1 mRNA level (9) and decrease insulin level compared with AhR knockout mice after glucose challenge (10). Furthermore, AhR activator TCDD can down-regulate GR level in HeLa cells (11). We suppose AhR and GR have oppositional functions on insulin-mediated glucose metabolism, berberine perturbs GR via activating AhR to moderate IR, although agonist of AhR may directly induce IR (12).
17-hydroxylase (Cyp17) is the key enzyme controlling ovary androgen synthesis. The activation of Cyp17 is the cause of the higher androgen level in PCOS. DEX increases the theca cell testosterone synthesis and Cyp17 mRNA expression (2). In contrast, chronic treatment of TCDD, could decrease ovarian Cyp17 gene expression in female rats(13). Further more, AhR knockout follicles from adult mice produce higher androgen level compared to wild type (14). These data indicate that AhR possibly antagonizes DEX’s effect with respect to ovary androgen synthesis. DEX increases the ovulation rate in women with unexplained infertility treated with clomiphene citrate(15). Dexamethasone-treated female rat has been found to release a larger number of oocytes at PMAS induced ovulation and thus to give birth to larger litters (16), indicate DEX can increase the follicle development, ovulation rate and the number of viable oocyte.
In contrast, TCDD treated rat shows fewer large preovulatory follicles and lower serum estradiol level (17). AhR knockout mice develop significantly more fully formed primordial follicles but fewer antral follicles than wild-type, with a morphology similar to the polycystic ovary(18). Although there is no evidence that AhR directly affects DEX-GR signaling during foliclegenesis and ovulation, however, both AhR and GR show counter-regulatory effects to each other.
Overall, AhR serves as a potential antagonist of GR during ovary steroidogenesis and folliculogenesis. The AhR knockout mice show ovary phenotypes of polysystic ovary syndrome, the relationship between AhR on PCOS deserves further investigation.
Wei Li, M.Sc.
Xiaoke Wu, M.D., Ph.D.
Department of Obstetrics and Gynecology
Key Laboratory of Gynecology
First Affiliated Hospital
Heilongjiang University of Chinese Medicine
Harbin, People’s Republic of China
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2. Zhao L, Li W, Han F, Hou L, Baillargeon JP, Kuang H, et al. Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro. Fertil Steril. 2010 ;13. (Epub ahead of print)
3. Wu XK, Zhou SY, Liu JX, Po¨lla¨nen P, Sallinen K, Ma¨kinen M. Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil Steril. 2003; 80:954–65.
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8. Vrzal R, Zdarilova A, Ulrichova J, Blaha L, Giesy JP , Dvorak Z, Activation of the aryl hydrocarbon receptor by berberine in HepG2 and H4IIE cells: Biphasic effect on CYP1A1. Biochem Pharmacol 2005; 70: 925-36.
9. Marchand A, Tomkiewicz C, Marchandeau JP, Boitier E, Barouki R, Garlatti M. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces insulin-like growth factor binding protein-1 gene expression and counteracts the negative effect of insulin. Mol Pharmacol. 2005;67:444-52.
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12. Nishiumi S, Yoshida M, Azuma T, Yoshida K, Ashida H, 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes. Toxicol Sci 2010;115:482-91.
13. Valdez KE, Shi Z, Ting AY, Petroff BK. Effect of chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin in female rats on ovarian gene expression . Reprod Toxicol. 2009;28:32-7.
14. Hernandez-Ochoa I, Barnett-Ringgold KR, Dehlinger SL, Gupta RK, Leslie TC, Roby KF, et al. The ability of the aryl hydrocarbon receptor to regulate ovarian follicle growth and estradiol biosynthesis in mice depends on stage of sexual maturity. Biol Reprod. 2010;83:698-706.
15. Moradan S, Ghorbani R. Dexamethasone in unexplained infertility. Saudi Med J. 2009 ;30 :1034-6.
16. Rockwell LC, Koos RD. Dexamethasone enhances fertility and preovulatory serum prolactin levels in eCG/hCG primed immature rats. J Reprod Dev. 2009;55:247-51.
17. Salisbury TB, Marcinkiewicz JL . Decreased response to PMSG-stimulated follicle growth in rats exposed to 2,3,7,8 tetrachloro-dibenzo-p-dioxin(TCDD) in utero. 2001;64:347.
18. Jamie C. Benedict, Tien-Min Lin, I. K. Loeffler, Richard E. Peterson, Jodi A. Flaws. Physiological Role of the Aryl Hydrocarbon Receptor in Mouse Ovary Development. Toxicol. Sci. 2000;56: 3.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.11.013