RESUMO
Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. The current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of the ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. However, fenofibrate, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against ß-amyloid and H2O2 toxicity independently from PPARα activation. In conclusion, OLE and similar drugs, acting either as PPARα agonists or via PPARα independent mechanisms, could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions.
RESUMO
Accumulating clinical evidence indicates extensive inter-individual variations in the effectiveness and adverse effects of standard treatment protocols, which are largely attributed to the multifactorial regulation of the hepatic CYP-dependent drug metabolism that is connected with either transcriptional or post-translational modifications. Age and stress belong to the most important factors in CYP gene regulation. Alterations in neuroendocrine responses to stress, which are associated with modified hypothalamo-pituitary-adrenal axis function, usually accompany ageing. In this light, ageing followed by a decline of the functional integrity of organs, including liver, a failure in preserving homeostasis under stress, increased morbidity and susceptibility to stress, among others, holds a determinant role in the CYP-catalyzed drug metabolism and thus, in the outcome and toxicity of pharmacotherapy. Modifications in the drug metabolizing capacity of the liver with age have been reported and in particular, a decline in the activity of the main CYP isoforms in male senescent rats, indicating decreased metabolism and higher levels of the drug-substrates in their blood. These factors along with the restricted experience in the use of the most medicines in childhood and elderly, could explain at an extent the inter-individual variability in drug efficacy and toxicity outcomes, and underscore the necessity of designing the treatment protocols, accordingly.
Assuntos
Sistema Enzimático do Citocromo P-450 , Fígado , Masculino , Animais , Ratos , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/metabolismo , Isoformas de Proteínas/metabolismoRESUMO
PURPOSE: Adipokines produced by adipose tissue have been found to be involved in the pathophysiology of metabolic and cardiovascular diseases. We aimed to investigate the relationships of resistin, retinol-binding protein 4 (RBP4) and adiponectin produced by epicardial adipose tissue with coronary artery disease (CAD) and cardiac structure and function. METHODS: Forty-one non-diabetic males scheduled for cardiothoracic surgery were examined. Anthropometric measurements, echocardiography, coronary angiography, and blood analysis were performed preoperatively. We measured the serum levels of resistin, RBP4, and adiponectin and their mRNA expression in thoracic subcutaneous adipose tissue and two epicardial adipose tissue samples, one close to left anterior descending artery (LAD) (resistin-LAD, RBP4-LAD, adiponectin-LAD), and another close to the right coronary artery (RCA) (resistin-RCA, RBP4-RCA, adiponectin-RCA). RESULTS: Left ventricular (LV) ejection fraction correlated negatively with adiponectin-LAD (rho = - 0.390, p = 0.025). The ratio of early to late diastolic transmitral flow velocity, as an index of LV diastolic function, correlated negatively with resistin-LAD (rho = - 0.529, p = 0.024) and RBP4-LAD (rho = - 0.458, p = 0.049). There was no difference in epicardial adipose tissue mRNA expression of resistin, RBP4, and adiponectin between individuals with CAD and those without CAD. When we compared the individuals with CAD in the LAD with those without CAD in the LAD, there was no difference in resistin-LAD, RBP4-LAD, and adiponectin-LAD. There was no difference in resistin-RCA, RBP4-RCA, and adiponectin-RCA between the individuals with CAD in the RCA and those without CAD in the RCA. CONCLUSION: Elevation of epicardial adipose tissue mRNA expression of adiponectin was associated with LV systolic dysfunction, while that of both resistin and RBP4 was linked to LV diastolic dysfunction.
Assuntos
Adiponectina , Doença da Artéria Coronariana , Masculino , Humanos , Resistina , Tecido Adiposo/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação ao Retinol/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/genética , Proteínas Plasmáticas de Ligação ao Retinol/metabolismoRESUMO
Oleuropein (OLE), the main constituent of Olea europaea, displays pleiotropic beneficial effects in health and disease, which are mainly attributed to its anti-inflammatory and cardioprotective properties. Several food supplements and herbal medicines contain OLE and are available without a prescription. This study investigated the effects of OLE on the main cytochrome P450s (P450s) catalyzing the metabolism of many prescribed drugs. Emphasis was given to the role of peroxisome proliferator-activated receptor α (PPARα), a nuclear transcription factor regulating numerous genes including P450s. 129/Sv wild-type and Ppara-null mice were treated with OLE for 6 weeks. OLE induced Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22, and Cyp2e1 mRNAs in liver of wild-type mice, whereas no similar effects were observed in Ppara-null mice, indicating that the OLE-induced effect on these P450s is mediated by PPARα. Activation of the pathways related to phosphoinositide 3-kinase/protein kinase B (AKT)/forkhead box protein O1, c-Jun N-terminal kinase, AKT/p70, and extracellular signal-regulated kinase participates in P450 induction by OLE. These data indicate that consumption of herbal medicines and food supplements containing OLE could accelerate the metabolism of drug substrates of the above-mentioned P450s, thus reducing their efficacy and the outcome of pharmacotherapy. Therefore, OLE-induced activation of PPARα could modify the effects of drugs due to their increased metabolism and clearance, which should be taken into account when consuming OLE-containing products with certain drugs, in particular those of narrow therapeutic window. SIGNIFICANCE STATEMENT: This study indicated that oleuropein, which belongs to the main constituents of the leaves and olive drupes of Olea europaea, induces the synthesis of the major cytochrome P450s (P450s) metabolizing the majority of prescribed drugs via activation of peroxisome proliferator-activated receptor α. This effect could modify the pharmacokinetic profile of co-administered drug substrates of the P450s, thus altering their therapeutic efficacy and toxicity.
Assuntos
Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Inativação Metabólica/efeitos dos fármacos , Glucosídeos Iridoides/farmacocinética , Oleaceae , PPAR alfa/metabolismo , Animais , Anti-Inflamatórios/farmacocinética , Cardiotônicos/farmacocinética , Sistema Enzimático do Citocromo P-450/classificação , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica , Camundongos , Compostos Fitoquímicos/farmacocinética , Medicamentos sob Prescrição/farmacocinéticaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The main pathophysiological mechanisms involve cholinergic neurotransmission, beta-amyloid (Αß) and Tau proteins, several metal ions and oxidative stress, among others. Current drugs offer only relief of symptoms and not a cure of AD. Accumulating evidence suggests that multifunctional compounds, targeting multiple pathophysiological mechanisms, may have a great potential for the treatment of AD. In this study, we report on the synthesis and physicochemical characterization of four quinoline-based metal chelators and their respective copper(II) complexes. Most compounds were non-toxic at concentrations ≤5 µM. In neuroprotection studies employing undifferentiated and differentiated SH-SY5Y cells, the metal chelator N2,N6-di(quinolin-8-yl)pyridine-2,6-dicarboxamide (H2dqpyca) appeared to exert significant neuroprotection against both, Aß peptide- and H2O2-induced toxicities. The copper(II) complex [CuII(H2bqch)Cl2].3H2O (H2bqch = N,N'-Bis(8-quinolyl)cyclohexane-1,2-diamine) also protected against H2O2-induced toxicity, with a half-maximal effective concentration of 80 nM. Molecular docking simulations, using the crystal structure of the acetylcholinesterase (AChE)-rivastigmine complex as a template, indicated a strong interaction of the metal chelator H2dqpyca, followed by H2bqch, with both the peripheral anionic site and the catalytic active site of AChE. In conclusion, the sufficient neuroprotection provided by the metal chelator H2dqpyca and the copper(II) complex [CuII(H2bqch)Cl2].3H2O along with the evidence for interaction between H2dqpyca and AChE, indicate that these compounds have the potential and should be further investigated in the framework of preclinical studies employing animal models of AD as candidate multifunctional lead compounds for the treatment of the disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Complexos de Coordenação/farmacologia , Fármacos Neuroprotetores/farmacologia , Quinolinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/toxicidade , Cobre/química , Cricetulus , Humanos , Peróxido de Hidrogênio/toxicidade , Ligantes , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/toxicidade , Ligação Proteica , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolinas/toxicidadeRESUMO
The CYP2D subfamily catalyses the metabolism of about 25% of prescribed drugs, including the majority of antidepressants and antipsychotics. At present, the mechanism of hepatic CYP2D regulation remains largely unknown. This study investigated the role of sex steroid hormones in CYP2D regulation. For this purpose, Cyp2d22 expression was assessed in the distinct phases of the estrous cycle of normocyclic C57BL/6J (WT) female mice. Cyp2d22 was also evaluated in ovariectomised WT and CYP2D6-humanized (hCYP2D6) mice that received hormonal supplementation with either 17ß-estradiol (E2) and/or progesterone. Comparisons were also made to male mice. The data revealed that hepatic Cyp2d22 mRNA, protein and activity levels were higher at estrous compared to the other phases of the estrous cycle and that ovariectomy repressed Cyp2d22 expression in WT mice. Tamoxifen, an anti-estrogenic compound, also repressed hepatic Cyp2d22 via activation of GH/STAT5b and PI3k/AKT signaling pathways. Both hormones prevented the ovariectomy-mediated Cyp2d22 repression. In case of progesterone, this may be mediated by inhibition of the PI3k/AKT/FOX01 pathway. Notably, Cyp2d22 mRNA levels in WT males were similar to those in ovariectomised mice and were markedly lower compared to females at estrous, a differentiation potentially regulated by the GH/STAT5b pathway. Sex steroid hormone-related alterations in Cyp2d22 mRNA expression were highly correlated with Hnf1a mRNA. Interestingly, fluctuations in Cyp2d22 in hippocampus and cerebellum followed those in liver. In contrast to WT mice, ovariectomy induced hepatic CYP2D6 expression in hCYP2D6 mice, whereas E2 and/or progesterone prevented this induction. Apparently, sex steroid hormones display a significant gender- and species-specific role in the regulation of CYP2D.
Assuntos
Família 2 do Citocromo P450/metabolismo , Regulação da Expressão Gênica/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Transdução de Sinais/genética , Animais , Citocromo P-450 CYP2D6/metabolismo , Estradiol/administração & dosagem , Ciclo Estral/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Progesterona/administração & dosagem , RNA Mensageiro/metabolismoRESUMO
Aldehyde hydrogenases (ALDHs) belong to a large gene family involved in oxidation of both endogenous and exogenous compounds in mammalian tissues. Among ALDHs, the rat ALDH1A7 gene displays a curious strain dependence in phenobarbital (PB)-induced hepatic expression: the responsive RR strains exhibit induction of both ALDH1A7 and CYP2B mRNAs and activities, whereas the nonresponsive rr strains show induction of CYP2B only. Here, we investigated the responsiveness of ALDH1A1, ALDH1A7, CYP2B1, and CYP3A23 genes to prototypical P450 inducers, expression of nuclear receptors CAR and pregnane X receptor, and structure of the ALDH1A7 promoter in both rat strains. ALDH1A7 mRNA, associated protein and activity were strongly induced by PB and modestly induced by pregnenolone 16α-carbonitrile in the RR strain but negligibly in the rr strain, whereas induction of ALDH1A1 and P450 mRNAs was similar between the strains. Reporter gene and chromatin immunoprecipitation assays indicated that the loss of ALDH1A7 inducibility in the rr strain is profoundly linked with a 16-base pair deletion in the proximal promoter and inability of the upstream DNA sequences to recruit constitutive androstane receptor-retinoid X receptor heterodimers. SIGNIFICANCE STATEMENT: Genetic variation in rat ALDH1A7 promoter sequences underlie the large strain-dependent differences in expression and inducibility by phenobarbital of the aldehyde dehydrogenase activity. This finding has implications for the design and interpretation of pharmacological and toxicological studies on the effects and disposition of aldehydes.
Assuntos
Família Aldeído Desidrogenase 1/biossíntese , Família Aldeído Desidrogenase 1/genética , Regulação Enzimológica da Expressão Gênica , Variação Genética/fisiologia , Animais , Masculino , Ratos , Ratos Wistar , Especificidade da EspécieRESUMO
Adrenoceptor (AR)-linked pathways belong to the major components of the stress response system and are associated with the pathophysiology of diseases within the spectrum of metabolic syndrome. In this study, the role of adrenoceptor stimulation in serum triglyceride (TG) regulation in mice was investigated. For this purpose, α1 -ARs were activated with phenylephrine (PH) and ß1/2 -ARs with isoprenaline (ISOP). Both AR agonists markedly reduced serum TG levels independently of PPARα activation. These drugs also significantly activated the hormone-sensitive lipase in the white adipose tissue indicating increased mobilization of TGs in this tissue. In addition, PH and ISOP up-regulated Lpl, Nr4A, Dgat1, Mttp, Aadac and Cd36 genes, critical in TG regulation, whereas the observed decrease in serum TG levels was independent of the hepatic very low-density lipoprotein (VLDL)-TG secretion. Interestingly, PH and ISOP also inactivated the hepatic insulin/PI3k/AKT/FoxO1 signaling pathway, holding a critical role in the regulation of genes involved in TG synthesis. Taken together, the findings of the present study indicate that stimulation of α1 - and ß1/2 -ARs markedly reduced serum TG steady-state levels as a result of alterations in TG synthesis, uptake, transport, hydrolysis, metabolism and clearance, an effect induced by PPARα independent mechanisms.
Assuntos
Tecido Adiposo Branco/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Triglicerídeos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Proteínas de Transporte/genética , Diacilglicerol O-Aciltransferase/genética , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/genética , Isoproterenol/farmacologia , Fígado/metabolismo , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , PPAR alfa/genética , Fenilefrina/farmacologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Esterol Esterase/genética , Triglicerídeos/sangueRESUMO
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-1ß, 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 ß1/2-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-1ß levels, whereas IL-1ß inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1ß. 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 ß1/2-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.
Assuntos
Mediadores da Inflamação/sangue , Receptores Adrenérgicos/metabolismo , Proteína Amiloide A Sérica/biossíntese , Estresse Psicológico/sangue , Estresse Psicológico/psicologia , Agonistas Adrenérgicos/farmacologia , Animais , Citocinas/sangue , Interleucina-1beta/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Estresse Psicológico/etiologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Oleuropein (OLE), a main constituent of olive, exhibits antioxidant and hypolipidemic effects, while it reduces the infarct size in chow- and cholesterol-fed rabbits. Peroxisome proliferator-activated receptor α (PPARα) has essential roles in the control of lipid metabolism and energy homeostasis. This study focused on the mechanisms underlying the hypolipidemic activity of OLE and, specifically, on the role of PPARα activation in the OLE-induced effect. Theoretical approach using Molecular Docking Simulations and luciferase reporter gene assay indicated that OLE is a ligand of PPARα. The effect of OLE (100 mg/kg, p.o., per day, ×6 weeks) on serum triglyceride (TG) and cholesterol levels was also assessed in adult male wild-type and Ppara-null mice. Molecular Docking Simulations, Luciferase reporter gene assay and gene expression analysis indicated that OLE is a PPARα agonist that up-regulates several PPARα target genes in the liver. This effect was associated with a significant reduction of serum TG and cholesterol levels. In contrast, OLE had no effect in Ppara-null mice, indicating a direct involvement of PPARα in the OLE-induced serum TG and cholesterol reduction. Activation of hormone-sensitive lipase in the white adipose tissue (WAT) and the liver of wild-type mice and up-regulation of several hepatic factors involved in TG uptake, transport, metabolism and clearance may also contribute in the OLE-induced TG reduction. In summary, OLE has a beneficial effect on TG homeostasis via PPARα activation. OLE also activates the hormone sensitive lipase in the WAT and liver and up-regulates several hepatic genes with essential roles in TG homeostasis.
Assuntos
Iridoides/farmacologia , PPAR alfa/agonistas , Triglicerídeos/sangue , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Glucosídeos Iridoides , Iridoides/química , Iridoides/metabolismo , Lipídeos/sangue , Luciferases/genética , Masculino , Camundongos Endogâmicos , Camundongos Mutantes , Simulação de Acoplamento Molecular , Olea/química , PPAR alfa/química , PPAR alfa/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genéticaRESUMO
Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Farmacocinética , Estresse Psicológico/enzimologia , Animais , HumanosRESUMO
Stress is a risk factor for several cardiovascular pathologies. PPARα holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPARα agonists are effective in raising HDL-cholesterol and lowering triglycerides, properties that reduce the risk for cardiovascular diseases. This study investigated the role of stress and adrenergic receptor (AR)-related pathways in PPARα and HNF4α regulation and signaling in mice following repeated restraint stress or treatment with AR-antagonists administered prior to stress to block AR-linked pathways. Repeated restraint stress up-regulated Pparα and its target genes in the liver, including Acox, Acot1, Acot4, Cyp4a10, Cyp4a14 and Lipin2, an effect that was highly correlated with Hnf4α. In vitro studies using primary hepatocyte cultures treated with epinephrine or AR-agonists confirmed that hepatic AR/cAMP/PKA/CREB- and JNK-linked pathways are involved in PPARα and HNF4α regulation. Notably, restraint stress, independent of PPARα, suppressed plasma triglyceride levels. This stress-induced effect could be attributed in part to hormone sensitive lipase activation in the white adipose tissue, which was not prevented by the increased levels of perilipin. Overall, this study identifies a mechanistic basis for the modification of lipid homeostasis following stress and potentially indicates novel roles for PPARα and HNF4α in stress-induced lipid metabolism.
Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Homeostase , Metabolismo dos Lipídeos , PPAR alfa/metabolismo , Estresse Psicológico/metabolismo , Animais , Biomarcadores/metabolismo , Colesterol/biossíntese , Colesterol/sangue , Deleção de Genes , Glucocorticoides/metabolismo , Fator 4 Nuclear de Hepatócito/deficiência , Fator 4 Nuclear de Hepatócito/genética , Hepatócitos/metabolismo , Masculino , Camundongos , Oxirredução , Receptores Adrenérgicos/metabolismo , Receptores de LDL/metabolismo , Restrição Física/efeitos adversos , Transdução de Sinais , Estresse Psicológico/sangue , Estresse Psicológico/patologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Regulação para CimaRESUMO
INTRODUCTION: The available evidence suggests that psychophysiological stress regulates a substantial number of factors, which in turn, can alter the pharmacokinetic parameters of a drug. AREAS COVERED: Due to the multi-factorial involvement of stress in the regulation of a drug's pharmacokinetic profile, this review has been limited to and focuses only on the impact of stress on drug metabolism. Specifically, the review presents studies which have indicated that psychophysiological stress can significantly modify the function of the major hepatic drug-metabolizing enzymes belonging to cytochrome P450s (CYP) family in a stress-specific and species-specific manner. Furthermore, the article discusses how stress related changes in CYP regulation appear to be mediated by glucocorticoids and epinephrine/norepinephrine. This can lead to an increased rate of metabolism of the majority of prescribed drugs and chemical pre-carcinogens. EXPERT OPINION: Apparently, psychophysiological stress has a significant impact on some of the major drug-metabolizing enzyme systems. Therefore, stress should be considered as an important factor affecting drug metabolism and pharmacokinetics, with the potential to significantly alter the outcome of drug therapy and toxicity. Despite the fact that the majority of data come from experimental studies, it is conceivable that the elimination of stress is an essential condition in order to ensure the optimal outcome of pharmacotherapy.
Assuntos
Preparações Farmacêuticas/metabolismo , Farmacocinética , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Interações Medicamentosas , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Regulação para CimaRESUMO
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 17ß-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-1α, ß-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.
Assuntos
Citocromo P-450 CYP2E1/biossíntese , Estradiol/farmacologia , Fígado/enzimologia , Progesterona/farmacologia , Animais , Western Blotting , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Antagonistas de Estrogênios/farmacologia , Ciclo Estral , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA/química , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT5/metabolismo , Tamoxifeno/farmacologiaRESUMO
Early maternal deprivation (MD) is an animal model of neurodevelopmental stress associated with a variety of abnormalities during adulthood. The present study investigated specific behavioral, neurochemical and neurobiological parameters related to dopaminergic and serotonergic function in adult rats subjected to early life MD. Behavioral responses, including the reaction to novelty, the response to d-amphetamine (d-AMP) and the susceptibility to apomorphine (APO) were evaluated in adulthood. Dopamine (DA) and serotonin (5-HT) levels, their metabolites along with their turnover ratios were assessed in distinct rat brain regions. The impact of MD on DARPP-32 protein, D2 and 5-HT2A receptor expression was also estimated in the same brain regions during adulthood. Our results indicated that MD rats were more reactive to novelty behavior and more sensitive to dopaminergic agonists compared to controls. MD rats displayed elevated dopaminergic and serotonergic function in the amygdala and prefrontal cortex, whereas in the striatum only the dopaminergic activity was also increased. Interestingly, MD induced a region-dependent modulation of D2, 5-HT2A receptor and DARPP-32 protein expression. Our findings clearly indicated that early MD stress produces long term behavioral impairments and region-dependent modifications in various neurochemical and neurobiological indices of dopaminergic and serotonergic function in brain regions holding critical roles in the pathophysiology of central nervous system disorders.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Expressão Gênica/efeitos dos fármacos , Privação Materna , Serotonina/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Apomorfina/farmacologia , Corpo Estriado/metabolismo , Dextroanfetamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/biossínteseRESUMO
Hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally responsible for the hypercorticosteronism remains unclear. The purpose of this study was to assess the effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis, to identify the locus in the HPA axis that is principally affected, and address the time-dependent effects of alterations in thyroid status. The functional integrity of each component of the HPA axis was examined in vitro and in situ in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given pharmacological dose (50 µg) of thyroxin for 7 or 60 days. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days. Basal plasma ACTH levels were similar to controls. Both hypothalamic CRH content and the magnitude of KCL- and arginine vasopressin (AVP)-induced CRH release from hypothalamic culture were increased in long-term hyperthyroid rats. There was a significant increase in the content of both ACTH and ß-endorphin in the anterior pituitaries of both short- and long-term hyperthyroid animals. Short-term hyperthyroid rats showed a significant increase in basal POMC mRNA expression in the anterior pituitary, and chronically hyperthyroid animals showed increased stress-induced POMC mRNA expression. Adrenal cultures taken from short-term hyperthyroid rats responded to exogenous ACTH with an exaggerated corticosterone response, while those taken from 60-day hyperthyroid animals showed responses similar to controls. The findings show that hyperthyroidism is associated with hypercorticosteronemia and HPA axis dysfunction that becomes more pronounced as the duration of hyperthyroidism increases. The evidence suggests that experimentally induced hyperthyroidism is associated with central hyperactivity of the HPA axis.
Assuntos
Hipertireoidismo/fisiopatologia , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipófise-Suprarrenal/patologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/metabolismoRESUMO
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 D2-dopaminergic systems in the regulation of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D. Blockade of D2-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 D2-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 1α, 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 D2-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.
Assuntos
Antipsicóticos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Receptores de Dopamina D2/fisiologia , Sulpirida/farmacologia , Animais , Antipsicóticos/efeitos adversos , Antagonistas dos Receptores de Dopamina D2 , Etanolaminas/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hormônios/sangue , Técnicas In Vitro , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Ratos , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Sulpirida/efeitos adversosRESUMO
Stress is a critical player in the regulation of the major cytochrome P-450s (CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the expression of CYP3A1 and CYP2C11 was increased in the liver of MD rats, whereas RS had no significant effect. In contrast, hepatic CYP2D1/2 activity was increased by RS, whereas MD did not affect it. The primary effectors of the stress system, glucocorticoids and epinephrine, highly induced CYP3A1/2. Epinephrine also induced the expression of CYP2C11 and CYP2D1/2. Further investigation indicated that AR-agonists may modify CYP regulation. In vitro experiments using primary hepatocyte cultures treated with the AR-agonists phenylephrine, dexmedetomidine, and isoprenaline indicated an AR-induced upregulating effect on the above-mentioned CYPs mediated by the cAMP/protein kinase A and c-Jun NH2-terminal kinase signaling pathways. Interestingly though, in vivo pharmacological manipulations of ARs using the same AR-agonists led to a suppressed hepatic CYP expression profile, indicating that the effect of the complex network of central and peripheral AR-linked pathways overrides that of the hepatic ARs. The AR-mediated alterations in CYP3A1/2, CYP2C11, and CYP2D1/2 expressions are potentially connected with those observed in the activation of signal transducer and activator of transcription 5b. In conclusion, stress and AR-agonists may modify the expression of the major CYP genes involved in the metabolism of drugs used in a wide range of diseases, thus affecting drug efficacy and toxicity.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hepatócitos/metabolismo , Receptores Adrenérgicos/metabolismo , Esteroide 16-alfa-Hidroxilase/metabolismo , Estresse Fisiológico , Estresse Psicológico/metabolismo , Agonistas Adrenérgicos/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Células Cultivadas , Corticosterona/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Família 2 do Citocromo P450 , Indução Enzimática/efeitos dos fármacos , Epinefrina/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Privação Materna , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos/química , Restrição Física/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Esteroide 16-alfa-Hidroxilase/genética , Estresse Psicológico/patologiaRESUMO
Strategies for prevention of venous thromboembolism in orthopaedic patients undergoing major lower limb surgery include pharmacological prophylaxis. Over the last three decades, the search for new safe and effective approaches for the prevention of venous thromboembolism in these patients has continued. Increased understanding of the haemostatic process has led to a clearer appreciation of the mechanisms of action of antithrombotic drugs already in use as well as the identification of new targets for novel drug development. As a result, the development of new anticoagulants has advanced rapidly over recent years. The molecular targets of several novel anticoagulants, and their effectiveness in early Phase II and Phase III trials are reviewed.