Benzo(α)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

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

doi:10.1016/j.lfs.2006.01.012

Cited by 17 publications

(19 citation statements)

References 26 publications

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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%

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%

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

et al. 2012

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“…This finding is consistent with previous reports supporting that CYP1A1 and CYP1A2 isozymes are, in part, differently regulated (Konstandi et al, 2006;Ioannides and Parke, 1990). Although CYP1A2 apoprotein was suppressed only in CD rats after PB, MROD activity was increased in both dietary cases.…”

Section: Discussionsupporting

confidence: 93%

Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

Konstandi

Segos

Galanopoulou

et al. 2008

J of Applied Toxicology

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Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CD prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathione-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB.

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“…These data are in line with previous reports supporting that CYP1A1 and CYP1A2 genes are, up to some extend, differently regulated [49]. Stress increased MROD induction after α 2 -blockade with atipamezole, while the drug alone had no effect.…”

Section: Discussionsupporting

confidence: 93%

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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Benzo(α)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

Cited by 17 publications

References 26 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

Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

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

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Benzo(α)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

Cited by 17 publications

References 26 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

Effects of choline‐deprivation on paracetamol‐ or phenobarbital‐induced rat liver metabolic response

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

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Product

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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