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  • br Regulatory roles of VDR on CYP


    Regulatory roles of VDR on CYP3A in different species
    Conclusion The up-regulatory effects of activated VDR on human CYP3A4 Rimonabant sale are clearly indicated in in vitro and ex vivo experiments, and the molecular mechanism is well elucidated. However, the clinical significance of related VDR polymorphisms and/or VDR-mediated CYP3A4 induction remains to be established. Mice and rats are two kinds of commonly used rodent animal models, in which the organ-specific and isoform-specific CYP3A induction by VDR ligands is also observed. It is noteworthy that most studies only focus on the mRNA level changes of CYP3As, but pay less attention to the changes of the relevant protein levels or metabolic activities, which might influence the pharmacokinetic profiles of CYP3A substrates. In particular, more in vivo evidence could be provided on VDR in the induction of CYP3A based on the Vdr KO mouse or rat models. Despite species discrepancies, the results from mice or rat experiments help to understand better the less focused pathway of CYP3A transcriptional regulation by VDR. As compared with the broad spectrum of chemicals known to serve as the ligands for PXR and CAR, the ligands of VDR are previously restricted to VD3 as well as its hydroxylated metabolites and the secondary bile Rimonabant sale LCA. Recently, the VDR-binding capacities of more compounds have been discovered, which show both nutritional and pharmacological significance. Although the affinities of these compounds towards VDR are much weaker than those of the natural ligands, these substances could be massively absorbed from foods and high local concentrations might be effective for VDR agonism. As VD3 is an important nutrient and an endogenous chemical, the interplay between VD3 and CYP3A4 should be a special focus, particularly under many pathological conditions and in chemotherapy.
    Introduction Fructus Corni, named Shan-Zhu-Yu in Chinese, is the dried sarcocarp of Cornus officinalis Sieb. et Zucc. It has been used for thousands of years as an important traditional Chinese medicine in China, which exhibits a number of biological activities, including immunological regulation, antishock, antiarrhythmia, antibiosis, hypoglycemic, etc (1), (2). Morroniside is one of the most important iridoid glycosides, which are extracted from sarcocarp of C. officinalis. Its chemical structure is shown in Fig. 1 (3). Morroniside has been proved to be effective in invigorating stomach (4), preventing diabetic angiopathies (5) and renal damage (6), inhibiting lipid metabolism and inflammation (7) and reducing bone resorption (8). In recent studies, it was also reported that morroniside had significant neuroprotective effect (9), (10), (11). Extensive studies have been carried out to investigate the pharmacokinetics of morroniside (3), (12), (13), but the direct relationship between morroniside and cytochrome P450 is unclear. The interaction between morroniside and cytochrome P450 may cause herb-drug interaction, and may potentially explain the use of herb-drug combination.