Background: 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.
Methods: 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
Results: 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.
Conclusion: 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.