[Frontiers in Bioscience 14, 4719-4745, January 1, 2009]

[Frontiers in Bioscience 14, 4719-4745, January 1, 2009]

Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio

Salvatore Modica, Elena Bellafante, Antonio Moschetta

Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti and Clinica Medica 'Augusto Murri', University of Bari, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction: Bile acids at a glance
3. Bile acid and xenobiotic metabolism phases
4. Nuclear receptors at the crossroad of bile acid and xenobiotic metabolism: 4.1. FXR; 4.2. PXR; 4.3. CAR
5. Regulation of bile acid and xenobiotic metabolism via FXR, PXR and CAR: 5.1. Feed-back repression of bile acid synthesis; 5.2. Bile acid and xenobiotic uptake (phase 0); 5.3. Bile acid and xenobiotic metabolism (phase I and phase II); 5.4. Bile acid and xenobiotic secretion (phase III); 5.5. Intestinal bile acid absorption
6. Clinical relevance of FXR, PXR and CAR in endobiotic and xenobiotic metabolism: 6.1. Cholestasis; 6.2. Cholesterol detoxification; 6.3. Drug-Drug interaction
7. Conclusions and Perspectives
8. Acknowledgments
9. References

1. ABSTRACT

Recent discoveries highlighted intriguing molecular pathways that regulate synthesis, uptake, metabolism and excretion of bile acids and xenobiotics. The knowledge of factors that control these homeostatic processes is of clinical relevance to better understand the drug-drug interacting scenario as well as to control cholesterol detoxification, cholestasis and other conditions. Here we present evidences for the existence of a gut-liver safety network whereby activation of the nuclear receptor FXR, PXR, CAR trio provides protection against accumulation of exogenous and metabolic noxae.