D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

Konstandi, Maria; Harkitis, Panagiotis; Kostakis, D.; Marselos, Marios; Johnson, Elizabeth O.; Lang, Matti A.

doi:10.1016/j.lfs.2007.09.026

Cited by 12 publications

(28 citation statements)

References 34 publications

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“…Among upstream signaling factors regulating the release of insulin in response to increased plasma glucose levels, dopamine plays a significant role; stimulation of D 2 -dopaminergic receptors in pancreatic ␤-cells suppresses insulin release (Rubí et al, 2005). In accordance with this finding and other earlier studies, we showed that blockade of D 2 -dopaminergic receptors stimulated insulin release and markedly down-regulated CYP2E1 expression (Konstandi et al, 2008). It is possible that the insulin/PI3K/Akt signaling pathway plays a determinant role in this regulation (Woodcroft et al, 2002).…”

Section: Introductionsupporting

confidence: 91%

“…For this purpose, rats were treated with the D 2 -dopaminergic receptor antagonist sulpiride (Konstandi et al, 2008), a typical antipsychotic drug that is used mainly for the treatment of psychosis associated with schizophrenia or major depressive disorder (Maitre et al, 1994). The direct effects of sulpiride on hepatocytes were assessed in vitro with primary hepatocyte cultures.…”

Section: Introductionmentioning

confidence: 99%

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D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

et al. 2012

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Various hormonal and monoaminergic systems play determinant roles in the regulation of several cytochromes P450 (P450s) in the liver. Growth hormone (GH), prolactin, and insulin are involved in P450 regulation, and their release is under dopaminergic control. This study focused on the role of D 2 -dopaminergic systems in the regulation of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D. Blockade of D 2 -dopaminergic receptors with either sulpiride (SULP) or 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol (L-741,626) markedly down-regulated CYP3A1/2, CYP2C11, and CYP2D1 expression in rat liver. This suppressive effect appeared to be mediated by the insulin/ phosphatidylinositol 3-kinase/Akt/FOXO1 signaling pathway. Furthermore, inactivation of the GH/STAT5b signaling pathway appeared to play a role in D 2 -dopaminergic receptor-mediated down-regulating effects on these P450s. SULP suppressed plasma GH levels, with subsequently reduced activation of STAT5b, which is the major GH pulse-activated transcription factor and has up-regulating effects on various P450s in hepatic tissue. Levels of prolactin, which exerts down-regulating control on P450s, were increased by SULP, which may contribute to SULP-mediated effects. Finally, it appears that SULP-induced inactivation of the cAMP/protein kinase A/cAMP-response element-binding protein signaling pathway, which is a critical regulator of pregnane X receptor and hepatocyte nuclear factor 1␣, and inactivation of the c-Jun N-terminal kinase contribute to SULP-induced down-regulation of the aforementioned P450s. Taken together, the present data provide evidence that drugs acting as D 2 -dopaminergic receptor antagonists might interfere with several major signaling pathways involved in the regulation of CYP3A, CYP2C, and CYP2D, which are critical enzymes in drug metabolism, thus affecting the effectiveness of the majority of prescribed drugs and the toxicity and carcinogenic potency of a plethora of toxicants and carcinogens.

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Section: Introductionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

et al. 2012

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“…The multifactorial and complex process of CYP2E1 regulation has been demonstrated by previous studies (22,29,37; Fig. 10) indicating that diverse factors may modify CYP2E1 expression at the levels of transcription (2, 9), mRNA stabilization (65,80), mRNA translation (32), protein synthesis (66), and protein degradation (54,56).…”

Section: Discussionmentioning

confidence: 71%

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Konstandi

Cheng

Gonzalez

2013

American Journal of Physiology-Endocrinology and Metabolism

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Konstandi M, Cheng J, Gonzalez FJ. Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver. Am J Physiol Endocrinol Metab 304: E1118 -E1128, 2013. First published April 2, 2013; doi:10.1152/ajpendo.00585.2012.-CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17␤-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1␣, ␤-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.Cyp2e1; 17␤-estradiol; progesterone; estrous cycle; mice PITUITARY HORMONES, in particular, growth hormone (GH), are considered critical in Cyp2e1 regulation. Previous studies revealed that pituitary hormone depletion by hypophysectomy resulted in Cyp2e1 upregulation in the liver of rats and GH supplementation normalized Cyp2e1 expression to constitutive levels by suppressing Cyp2e1 transcription (11,28,70,71,80). It is of interest to note that sex steroid hormones target complex regulatory dynamics including GH secretion. On the one hand, they augment GH-secretory burst by amplifying feedforward [via both GH-releasing hormone, GH-releasing peptide(s)] and on the other hand they attenuate feedback (imposed by somatostatin and GH). The role of testosterone is less clear (49,67). Previous studies in humans and experimental animals presented contradictory findings regarding sex differentiation in CYP2E1 constitutive expression and the role of sex steroid hormones in this regulation (5,11,29,33,34,59). This contradiction is probably du...

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“…METH increase synaptic levels of the monoamines Dopamine (DA), serotonin and Norepinephrine (NE) (Sofuoglu and Sewell, 2009). It has been demonstrated that dopaminergic system can regulate CYP isoenzymes expression in liver by altering levels of pituitary hormones and cytokine (Wojcikowski, 2004;Wojcikowski et al, 2007;2008;Konstandi et al, 2008). Psychostimulant amphetamine has been shown to cause a large increase in corticosterone concentration leading to a substantial rise in CYP3A activity and protein level by activating PXR (Wojcikowski et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Dopamine is one of the most important endogenous neurotransmitters as well as an important endogenous substrate of SULTs (Yasuda et al, 2009;Salman et al, 2009;Lu et al, 2005). It has been demonstrated that the expression of CYPs can be regulated by dopamine receptor-linked signaling pathway by changing the hormone (GH, thyroid hormones, glucocorticoids and so on) levels in vivo (Wojcikowski, 2004;Wojcikowski et al, 2007;2008;Konstandi et al, 2008). CNS psychostimulants regulation of the expression of SULTs is not studied.…”

Section: Introductionmentioning

confidence: 99%

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

Zhou¹

2010

American Journal of Pharmacology and Toxicology

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Problem statement: Sulfotransferases (SULTs) are important phase II drug metabolizing enzymes. They also regulate the biological activities of various hormones. To the best of our knowledge, psychostimulants regulation of SULTs is basically not studied except one article reported that Methamphetamine (METH) treatment induced rat amygdale rSULT1A1 mRNA 4.3 fold by using microarray method to identify a series of candidate genes after single-dose METH treatment. The psychostimulant METH is used to treat disorders such as attention deficit, narcolepsy and obesity. It is also a highly addictive drug that causes serious social problems. The abuse of this drug leads to the damage of monoaminergic systems in the mammalian brain. It is important to understand how SULT expressions are regulated by psychostimulants. Approach: This study was performed to evaluate the effect of METH on SULT gene expressions in rat liver and brain. METH (0, 1, 5, 20 mg kg −1 day −1 ) was used to treat male and female rats for 7 days by oral administration. Rat livers and brains were collected 24 h after the final drug treatment. Western blot and real-time RT-PCR were used to investigate the effect of METH on SULT protein and mRNA expression, respectively, in rat liver and brain. Results: Proteins and mRNAs of rSULT1A1, rSULT2A1 and rSULT1E1 were induced in liver and brain of both male and female rats following METH treatment. rSULT1E1 was induced at much higher level compared to that of rSULT1A1 and rSULT2A1. Brain inductions were found to be much higher than those found in liver. Conclusion: These data suggest an important role of the central dopaminergic system in the regulation of liver and brain rSULT expressions.

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D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

Cited by 12 publications

References 34 publications

D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

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D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

Cited by 12 publications

References 34 publications

D2-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

D2-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

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Product

Resources

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D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D

D₂-Dopaminergic Receptor-Linked Pathways: Critical Regulators of CYP3A, CYP2C, and CYP2D