The regulation of human hepatic drug transporter expression by activation of xenobiotic-sensing nuclear receptors

Introduction: If a drug is found to be an inducer of hepatic drug metabolizing enzymes via activation of nuclear receptors such as pregnane X receptor (PXR) or constitutive androstane receptor (CAR), it is likely that drug transporters regulated through these same receptors will be induced as well. This review highlights what is currently known about the molecular mechanisms that regulate transporter expression and where the research is directed.

Areas covered: This review is focused on publications that describe the role of activated hepatic nuclear receptors in the subsequent regulation of drug uptake and/or efflux transporters following exposure to xenobiotics.

Expert opinion: Many of the published studies on the role of nuclear receptors in the regulation of drug transporters involve non-human test animals. But due to species response differences, these associations are not always applicable to humans. For this reason, some relevant human in vitro models have been developed, such as primary or cryopreserved human hepatocytes, human liver slices, or HepG2 or HuH7 cell lines transiently or stably transfected with PXR expression and reporter constructs as well as in vivo models such as PXR-humanized mice. These human-relevant test systems will continue to be developed and applied for the testing of investigational drugs.     

Epigenetic regulation of nuclear steroid receptors

Histone modifier proteins have come to the forefront in the study of gene regulation. It is now known that histone methyltransferases, acetytransferases, kinases, ubiquitinases, deacetylases and demethylases orchestrate expression of target genes by modifying both histone and non-histone proteins. The nuclear receptor (NR) superfamily govern such diverse biological processes as development, physiology and disease, including human cancer. The involvement of NR in complexes with coactivators and corepressors is necessary for regulation of target genes. This review focuses on the newly recognized interactions between the NR and histone modifying enzymes. In addition to regulating histones, the histone modifying proteins directly modify and thereby regulate NR activity. In the same manner that signaling platforms exist within the histone tails that are post-translationally processed by histone modifying proteins, cascades of post-translational modification have been identified within the NR that coordinate their activity. This review focuses on the regulation of the NR estrogen receptor (ERalpha), androgen receptor (AR) and peroxisome proliferator activated receptor-gamma (PPARgamma), given their role in tumor onset and progression.     

Alpha-adrenergic receptors in the regulation of liver functions

Rat liver contains 80% alpha 1 and 20% alpha 2 receptors. The role of adrenergic regulation of liver functions was studied by administration of antagonist and agonist pharmaca. Female rats were treated with the selective alpha 1 receptor blocker prazosin. A transitory inhibition of microsomal monooxygenases was observed after 5 days which was terminated at the 12 day. A 18.7% loss of glycogen was measured at this time indicating a slight adrenergic glycogenolytic effect. Dihyd 50-ergocryptime an equal lebocker of alpha 1 alpha 2 receptori preserved glycogen content and has not impaired liver functions. Agonist epinephrine inhibited monooxygenase functions and mobilised 75% of hepatic glycogen. Simultaneous administration of prazosin with epinephrine resulted into glycogen loss due to alpha 2 receptor stimulation. Dihydroergocryptine antagonised rather the metabolic actions of epinephrine. We have established that alpha 2 receptors are also involved in hepatic carbohydrate metabolism.     

Nuclear receptors and their relevance to diseases related to lipid metabolism

Drugs that target the nuclear hormone receptor family constitute one of the largest and most potent groups of pharmaceuticals currently in use. However, although many of these human nuclear receptors have been clearly demonstrated to be key sensors and regulators of lipid metabolism, the full pharmacological potential of this drug target class has not been fully explored. There are two main reasons for this. First, a rationale approach is needed to identify pharmacologically selective drug candidates to nuclear receptors that have a large therapeutic window between the beneficial effects and the unwanted side effects. This appears to apply to all ligand-regulated nuclear receptors, including those nuclear receptors more recently proposed as novel targets for diseases related to lipid metabolism such as the peroxisome proliferator-activated receptors, liver X receptors and farnesoid X-activated receptor. The second reason is that any sub-group of nuclear receptors important for the regulation of lipid metabolism might be pharmacologically inaccessible by conventional low molecular weight compounds, owing to the lack of a classical ligand-binding-pocket, as recently revealed by X-ray crystallography. Accordingly, targeting of classical nuclear receptor family members with better characterized endocrinology and roles in lipid metabolism, such as the thyroid and steroid hormone receptors, could become of renewed pharmacological interest, as these targets provide well-characterized alternatives to the more recently discovered nuclear receptors.     

咪唑啉结合位点及受体与心血管功能

人及大鼠心肌细胞存在 2 型咪唑啉结合位点 ,多种动物的血管平滑肌存在 1 型和 2 型咪唑啉结合位点 ,其中 2 型咪唑啉结合位点可能参与血管平滑肌的增殖。支配心血管系统的交感神经末梢存在突触前咪唑啉受体 ,激动该受体抑制NE的释放。与多数咪唑啉类化合物不同 ,莫索尼定对突触前咪唑啉受体无效 ,而大麻受体拮抗剂SR141716A对该受体具有拮抗作用。已经证实多数咪唑啉类化合物具有抗心律失常作用 ;咪唑啉受体的内源性配基胍丁胺降低动物窦房结起搏细胞的放电频率 ,延长人与动物心肌细胞的动作电位时程 ,对异丙肾上腺素诱发的后除极具有抑制作用。但是 ,咪唑啉类和胍类化合物非竞争性抑制心血管系统的KATP通道 ,可能干扰IK .ATP的心脏保护作用。     

Herbal or natural medicines as modulators of peroxisome proliferator-activated receptors and related nuclear receptors for therapy of metabolic syndrome

The use of herbal or natural medicines for the treatment of various disorders has a long and extensive history. Many of these herbal medicines are finding their way onto the world market as alternatives to prescribed drugs currently available to treat various disorders/ailments. In particular, hyperlipidaemia is a major risk factor for atherosclerotic coronary vascular disease, which can culminate in mortality in diabetes mellitus. There is overwhelming evidence that patients with type 2 diabetes mellitus often have metabolic syndrome and require a multifactorial intervention including aggressive treatment of arterial hypertension and dyslipidaemia to prevent cardiovascular complications. One of the most active areas of metabolic research into potential treatments is in the role of nuclear receptors as therapeutic targets for both glucose and lipid metabolism. The purpose of this review is to highlight the recent advances made by pharmaceutical and research organizations in identifying biologically active compounds from natural plant products capable of modulating nuclear receptors such as peroxisome proliferator-activated receptors and, to a lesser extent, liver X receptor and farnesoid X receptor. The specific features presented by these receptors provide an in-depth insight into the pathogenesis of metabolic disease and thus, a means of establishing potential mechanisms of action with traditional medicine. In hindsight, the review offers valuable information for rational drug design using known active compounds of plant origin. Further research may ultimately lead to a reduction in both the chronic microvascular complications of type 2 diabetes mellitus and the risk of cardiovascular disease and metabolic syndrome with the use of traditional medicine.     

NK细胞及其受体在肝纤维化中的作用

免疫系统在肝纤维化的发展过程中起到重要的作用,近年来的研究发现,NK细胞及其受体积极参与了抑制肝纤维化的过程,NK细胞对活化型肝星状细胞具有靶向性杀伤作用。该文综述NK细胞及其受体在肝纤维化中的作用,期望NK细胞能成为今后治疗肝纤维化研究中的一个新的药物干预靶标。