title: Bile Acids as Novel Pharmacological Agents: The Interplay Between Gene Polymorphisms, Epigenetic Factors and Drug Response.
abstract: The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging.
  
  
  
  The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome.
  
  
  
  Most effects of bile acids are mediated by both nuclear and G protein-coupled receptors. Three natural bile acids have already been registered for the use in humans, but various semi-synthetic bile acid analogues with improved pharmacokinetic and pharmacodynamic properties have been developed, which opens up new avenues in pharmacotherapy. Many efforts have been made to evaluate the impact of nuclear receptors on inter-individual variation in responses to drugs, since nuclear receptors are significant mediators between environmental stimuli and pharmacokinetics. Genetic variation of bile acid-activated receptors is associated with both benign and malignant diseases, in terms of disease risk and severity, but also with pharmacokinetics and therapy outcome. Furthermore, the activity of these receptors may be masked or amplified by epigenetic modifications.
  
  
  
  Both genetic and epigenetic factors may alter complex and intricate network of bile acid signaling pathways, contributing to the development of several metabolic and non-metabolic diseases and altered activities of drug-metabolizing enzymes and transporters. These polymorphisms and epigenetic modifications may also impact the effectiveness and pharmacokinetics of bile acid analogues, which must be taken into account during the development of these compounds as novel therapeutic agents.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Pavlovic
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Stanimirov
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
authors.forename: Momir
authors.initials: M
authors.lastname: Mikov
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009765:Obesity / Q000188:drug therapy / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects* / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear
keywords: Bile acids; Farnesoid X receptor; TGR5; drug development; epigenetics; nuclear receptors; pharmacogenetics; polymorphisms