Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Departments of Medicine (H.L., S.M.), Molecular Pharmacology (S.M.), and Genetics (S.M.), Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Departments of Medicine (H.L., S.M.), Molecular Pharmacology (S.M.), and Genetics (S.M.), Albert Einstein College of Medicine, Bronx, New York, USA
Drug Metab Dispos. 2023 Feb;51(2):219-227. doi: 10.1124/dmd.122.000860. Epub 2022 Oct 2.
Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor-modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research. SIGNIFICANCE STATEMENT: Xenobiotic receptors (XRs) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors but also as a response to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.
异源生物受体，如孕烷 X 受体，调节多种宿主生理途径，包括异源生物代谢、某些细胞代谢和先天免疫。这些配体依赖性核因子通过基因组识别特定启动子和基因转录激活来调节基因表达。天然或内源性配体通常与这类受体无关；然而，由于这些受体在肝脏和肠道中以细胞类型特异性的方式表达，因此最近人们已经在努力鉴定微生物衍生的代谢物作为这些受体的配体。一般来说，这些代谢物被认为是弱的微摩尔亲和力配体。本期刊周年纪念迷你综述重点介绍了从潜在非毒性微生物代谢物中衍生化学模拟物的最新进展，这些模拟物有朝一日可能被开发为治疗异源生物受体修饰病理生理学的药物。本综述将包括我们对该领域的看法，并为未来的研究推荐某些方向。意义陈述：异源生物受体 (XR) 调节宿主药物代谢、细胞代谢和免疫。它们在宿主肠道中的存在使它们不仅能够作为外源性生物传感器发挥作用，还能够对肠道中存在的复杂代谢环境做出反应。具体来说，本综述重点描述了微生物代谢物-XR 相互作用，以及将这些发现转化为新型化学模拟物的发现，作为未来治疗炎症性肠病等疾病的潜在药物。
