oa Editorial [Hot Topic:Cross-Talk Between Endogenous Compounds and Regulatory Pathways of Drug Metabolism Guest Editor: Zdenek Dvorak]

The expression and activity of drug-metabolizing enzymes (DME) is influenced by variety of physiological factors (e.g. age, sex, pregnancy, menstrual cycle) and patho-physiological states of human organism (e.g. inflammation, infection, cancer, diabetes). Environmental factors (chemicals, radiation, microorganisms etc.) and gene polymorphisms have a great impact on activity of DME. Regulation of DME at molecular level is very complex and involves multiple mechanisms, including proteasome-mediated degradation, posttranslational regulation, transcriptional and post-transcriptional regulation. The principles of transcriptional regulation of DME were elucidated mainly in 90s'. In particular, the discovery of xenosensors AhR (aryl hydrocarbon receptor), PXR (pregnane X receptor) and CAR (constitutive androstane receptor), was a breakpoint in that research. Xenosensors were initially considered as orphan receptors that regulate only DME. However, all xenosensors were “deorphanized” at this time and demonstrated to regulate many other genes besides DME. For instance, endogenous ligands for AhR are metabolic intermediates such as bilirubin, biliverdin, indirubin, indole (tryptophan derivatives) and arachidonic acid derivatives. It is known that AhR plays many endogenous functions such as regulating the cell cycle and proliferation, immune response, circadian rhythm, tumor promotion etc. Examples of AhR-driven genes other than DME are AhRR, TGFβ, p27, IL-1β, Jun and Bax. Similarly PXR and CAR have many endogenous functions and they regulate metabolism of lipids, carbohydrates, cholesterol and bile acids. Consistently, examples of target genes for PXR and CAR, others than DME, are ApoA1 and amino levulinate synthase 1 (ALAS-1), respectively. Putative endogenous ligands for PXR (vitamin E, vitamin K, beta-carotene, bile acids) and CAR (farnesol) were identified as far. Taken together, deorphanization of xenosensors and identification of their role in intermediary metabolism and cell physiology, defined a relation between metabolism of xenobiotics and intermediary metabolism at molecular level. In the course of time, it was more and more clear that important regulators of DME are also typical regulators of intermediary metabolism, such as GR (glucocorticoid receptor), VDR (vitamin D receptor), ER (estrogen receptor), RAR (retinoic acid receptor) and RXR (retinoic X receptor), via their natural and synthetic ligands. In addition, many other endogenous compounds including inflammatory cytokines, growth factors, lipids, neurotransmitters, eicosanoids etc. influence the expression of DMEs. Hence, a reciprocal relation between endogenous compounds and metabolism of xenobiotics is defined in that way. There exist mutual interactions between xenoreceptors, steroid receptors and nuclear receptors by several mechanisms, usually called cross-talks. Cross-interactions or cross-talks between signaling pathways for two or more receptors result in functional molecular and physiological consequences. Cross-talks between two receptor-controlled pathways may occur by several mechanisms, comprising “sharing the ligand” (e.g. miconazole is agonist for PXR but at the same time antagonist for GR), “sharing the response element” (e.g. PXR and CAR share several response elements in CYP3A4 promoter), “regulatory cascade” (e.g. GR up-regulates transcriptionally PXR and CAR), “sharing the co-activator” (e.g. AhR that is transcriptional co-activator of ER) or “metabolic cascade” (e.g. CAR up-regulates UGT1A1, which in turn inactivates thyroid receptor ligands T3 and T4). The present issue of Current Drug Metabolism focuses on several aspects of mutual interaction between endobiotics and xenobiotics regulatory pathways.