Stress-mediated modulation of B(α)P-induced hepatic CYP1A1: role of catecholamines

Konstandi, Maria; Johnson, Elizabeth O.; Marselos, Marios; Kostakis, D.; Fotopoulos, Andreas; Lang, Matti A.

doi:10.1016/j.cbi.2003.10.007

Cited by 27 publications

(28 citation statements)

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“…An increasing body of evidence suggests that central and peripheral catecholaminergic systems play an important role in the regulation of drug-metabolizing enzymes, including the P450s (Konstandi et al, 2004(Konstandi et al, , 2005(Konstandi et al, , 2006Daskalopoulos et al, 2012). In accordance with this, the data in the present study clearly indicated a critical role for the dopaminergic pathways in P450 regulation.…”

Section: Discussionsupporting

confidence: 89%

“…Conversely, up-regulation of critical enzymes may accelerate the metabolism of drug substrate, thus leading to reduced pharmacological outcomes for the drug (Konstandi et al, 2005;Daskalopoulos et al, 2012). It is important, particularly for multidrug therapies, to be aware of the possibilities of drugdrug interactions that might lead to reduced or increased drug efficacy, severe toxicity, and/or tumorigenesis (Gonzalez and Gelboin, 1994;Guengerich, 2003;Konstandi et al, 2004;Pelkonen et al, 2008). Some of the most important P450 enzymes for hepatic phase I drug metabolism are members of the CYP3A, CYP2C, and CYP2D subfamilies (Ingelman-Sundberg, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Central and peripheral catecholaminergic systems have been determined to regulate P450 expression (Konstandi et al, 1998(Konstandi et al, , 2004Rendic and Guengerich, 2010;Daskalopoulos et al, 2012). In addition, previous studies clearly indicated critical roles for hormones, such as growth hormone (GH) (Waxman and O'Connor, 2006), thyroid hormones (Takahashi et al, 2010), and insulin (Kim and Novak, 2007), in the regulation of various hepatic P450s (Daskalopoulos et al, 2012).…”

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: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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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“…Previous studies have shown that psychological and physical stress is involved in the regulation of CYP1A1 and CYP1A2 [11][12][13][14]. In particular, repeated restraint stress, an experimental model of psychological and physical stress [15,16], has been found to modify both the constitutive and benzo( α )pyreneinduced CYP1A2-dependent 7-methoxyresorufin-O-dealkylase (MROD) activity [12,13].…”

mentioning

confidence: 99%

“…1). In particular, the up-regulating effect of stress on CYP1A1 induction appears to be mediated mainly by peripheral catecholamines, while central noradrenergic pathways appear to be indirectly involved in a down-regulating effect of stress [14]. We hypothesize that the stress-induced release of noradrenaline may play a critical role in the regulation of the genes under investigation during stress [11,12,17,25,26].…”

mentioning

confidence: 99%

Predominant Role of Peripheral Catecholamines in the Stress‐Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene

Konstandi¹,

Lang

Kostakis³

et al. 2007

Basic Clin Pharma Tox

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Abstract:The potential involvement of catecholamines and in particular of α 2 -adrenoceptor-related signalling pathways, in the regulation of drug-metabolizing enzymes by stress was investigated in Wistar rats after exposure to the environmental pollutant benzo( α )pyrene. For this purpose, total cytochrome P450 content, the CYP1A2 mRNA levels, 7-methoxyresorufin-O-dealkylase (MROD), 7-pentoxyresorufin-O-dealkylase (PROD) and p-nitrophenol hydroxylase activity levels were determined in the livers of rats exposed to repeated restraint stress after treatment with benzo( α )pyrene coupled with pharmacological manipulations of peripheral and/or central catecholamines and α 2 -adrenoceptors. The data show that stress is a significant factor in the regulation of CYP1A2 induction and that catecholamines play a central role in the stress-mediated modulation of hepatic CYP1A2 inducibility by benzo( α )pyrene. The up-regulating effect of stress on benzo( α )pyrene-induced CYP1A2 gene expression was eliminated after a generalized catecholamine depletion with reserpine. Similarly, in a state where only peripheral catecholamines were depleted and central catecholamines remained intact after guanethidine administration, the up-regulating effect of stress was eliminated. It is apparent that stress up-regulates the induction of CYP1A2 by benzo( α )pyrene mainly via peripheral catecholamines, while central catecholamines hold a minor role in the regulation. Pharmacological manipulations of α 2 -adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of α 2 -adrenoceptors with atipamezole and dexmedetomidine respectively, eliminated the up-regulating effect of stress on CYP1A2 benzo( α )pyrene-induced expression, while it enhanced MROD activity. In contrast, stress and pharmacological manipulations of catecholamines and α 2 -adrenoceptors did not affect total P450 content, the CYP2B1/2-dependent PROD and the CYP2E1-dependent p-nitrophenol hydroxylase activities. In conclusion, stress is a significant factor in the regulation of the CYP1A2 inducibility by benzo( α )pyrene, which in turn is involved in the metabolism of a large spectrum of toxicants, drugs and carcinogenic agents. Although the mechanism underlying the stress effect on CYP1A2 induction has not been clearly elucidated, it appears that peripheral catecholamines hold a predominant role, while central catecholamines and in particular, central noradrenergic pathways hold a minor role.

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Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis

et al. 2019

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Rationale Stressful life events are suggested to contribute to the development of various pathologies, such as cardiovascular disorders, whose etiopathogenesis is highly associated with elevated levels of serum amyloid A (SAA) proteins. SAA synthesis in the liver is regulated by a complex network of cytokines acting independently or in concert with various hormones/stimulants including the stress-activated sympathetic nervous system. Objective This study aims to investigate the underlying mechanisms that regulate the stress-induced hepatic synthesis of SAA, with particular focus on adrenoceptors (AR), major components of the sympathoadrenal response to stress. Methods and results We demonstrated that repeated stress elevates IL-1β, IL-6, and TNFα serum levels in mice, accompanied by increased synthesis and secretion of hepatic SAA1/2 and SAA3, an effect that was blocked by AR antagonists. Moreover, stimulation of α1 - and β1/2-ARs mimics the stress effect on SAA1/2 regulation, whereas α2-AR stimulation exhibits a relatively weak impact on SAA. In support of the essential cytokine contribution in the AR-agonist induced SAA production is the fact that the anti-inflammatory drug, sodium salicylate, prevented the AR-stimulated hepatic SAA1/2 synthesis by reducing IL-1β levels, whereas IL-1β inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1β. Interestingly, the AR-driven SAA3 synthesis was elevated by sodium salicylate in a TNFα-dependent way, supporting diverse and complex regulatory roles of cytokines in SAA production. In contrast to α1/α2-AR, the β1/2-AR-mediated SAA1/2 and SAA3 upregulation cannot be reversed by fenofibrate, a hypolipidemic drug with anti-inflammatory properties. Conclusion Taken together, these findings strongly support a critical role of the AR-stimulated inflammatory response in the hepatic SAA production under stressful conditions, highlighting distinct AR type-specific mechanisms that regulate the hepatic synthesis of SAA1/2 and SAA3.

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Stress-mediated modulation of B(α)P-induced hepatic CYP1A1: role of catecholamines

Cited by 27 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

Predominant Role of Peripheral Catecholamines in the Stress‐Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene

Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis

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Stress-mediated modulation of B(α)P-induced hepatic CYP1A1: role of catecholamines

Cited by 27 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

Predominant Role of Peripheral Catecholamines in the Stress‐Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene

Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis

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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