Bile Acids, Nuclear Receptors and Cytochrome P450

Abstract

This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives.

Decrease in major secondary bile acid, hyodeoxycholic acid, was the main alteration in hepatic bile acid compositions in a hypertensive nonalcoholic fatty liver disease model

“…The main limitation of our study is the difference in BA compositions between humans and the animal SHR model. First, HDCA does not usually exist in the human liver, but we showed that the decrease in HDCA was the major alteration in a hypertensive NAFLD rat model [10][11][12]. HCA, HDCA, alpha-MCA, beta-MCA, and omega-MCA commonly constitute the hepatic BAs in rats; however, these BAs do not usually exist in the human liver [10][11][12].…”

Review article: clinical pharmacology of current and investigational hepatitis B virus therapies

“…19 The mechanism for the small reduction in C max is unclear, but bile acids (which are increased with bulevirtide) may induce organic anion transporter (OAT) 3. 20 It is unclear whether the other HBV NAs, entecavir and TAF, would be affected.…”

“…19 Increased conjugated taurine bile acids are associated with inducing CYP(3A4) and drugtransporters through stimulation of nuclear receptors. 20 As these bile acids are increased (see below) when bulevirtide is used, this could also mean that there is a DDI in vivo that is not detected in vitro. 20 Additional "cocktail" probe studies performed in vivo may shed light on the DDI potential of bulevirtide.…”

“…20 As these bile acids are increased (see below) when bulevirtide is used, this could also mean that there is a DDI in vivo that is not detected in vitro. 20 Additional "cocktail" probe studies performed in vivo may shed light on the DDI potential of bulevirtide. Cocktail studies use recognised inhibitors, inducers and substrates of CYP enzymes or drug transporters to determine the potential for compounds to participate as victims or perpetrators in drug-drug interactions.…”

Plasma bile acid changes in type 2 diabetes correlated with insulin secretion in two‐step hyperglycemic clamp

“…Type 2 diabetes mellitus (T2DM), which is characterized by impaired insulin sensitivity and progressively declining insulin secretion capacity, is a worldwide health problem . Recently, bile acids (BAs), acting through G‐protein‐coupled bile acid receptor 1 (GPBAR1; also known as TGR5) and nuclear receptors (farnesoid X receptor [FXR], pregnane X receptor [PXR] and vitamin D receptor [VDR]), have been recognized as important signals for maintaining metabolic homeostasis, and this system has been mined for novel targets for pharmaceutical intervention in metabolic disorders such as T2DM . The pleiotropic roles of BA signaling in the regulation of metabolism include reducing hepatic lipid accumulation and glucose output, promoting thermogenesis via adipose browning, and stimulating incretin and insulin secretion …”