Interplay between cholesterol and drug metabolism.
Cholesterol biosynthetic and metabolic pathways contain several branching points towards physiologically active molecules, such as coenzyme Q, vitamin D, glucocorticoid and steroid hormones, oxysterols, or bile acids. Sophisticated regulatory mechanisms are involved in maintenance of the homeostasis of not only cholesterol but also other cholesterogenic molecules. In addition to endogenous cues, cholesterol homeostasis needs to accommodate also to exogenous cues that are imported into the body, such as chemicals and medications. Steroid and nuclear receptors together with sterol regulatory element-binding protein (SREBP) mediate the fine tuning of biosynthetic and metabolic routes as well as transports of cholesterol and its derivatives. Similarly, drug/xenobiotic metabolism is the subject to the feedback regulation of cytochrome P450 enzymes and transporters. The regulatory mechanisms that maintain the homeostasis of cholesterogenic molecules and are involved in drug metabolism share similarities. Cholesterol and cholesterogenic compounds (bile acids, glucocorticoids, vitamin D, etc.) regulate the xenosensor signaling in drug-mediated induction of the major drug-metabolizing cytochrome P450 enzymes. The key cellular receptors, pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and glucocorticoid receptor (GR) provide a functional cross-talk between the pathways maintaining cholesterol homeostasis and controlling the expression of drug-metabolizing enzymes. These receptors serve as metabolic sensors, resulting in a coordinate regulation of cholesterogenic compounds metabolism and of the defense against xenobiotic and endobiotic toxicity. Herein we present a comprehensive review of functional interactions between cholesterol homeostasis and drug metabolism involving the main nuclear and steroid receptors.
Rezen
Tadeja
T
Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Zaloska 4, SI-1000 Ljubljana, Slovenia.
Rozman
Damjana
D
Pascussi
Jean-Marc
JM
Monostory
Katalin
K
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism
D001647:Bile Acids and Salts; D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol