As compared with the broad spectrum of chemicals known
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 C598-0466 receptor 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. Using a probe substrate to determine the metabolic activities of cytochrome P450 is used widely in present drug–drug interaction studies. In this study, the effects of morroniside on the activity, mRNA and protein expression of CYP3A were investigated ex vivo by using rat liver microsomes. The effects of morroniside on the metabolism of midazolam, the probe substrate of CYP3A, were investigated in vivo. Combined ex and in vivo parameters might better reveal the potential of direct induced effects of morroniside on CYP3A in rats.
Materials and methods
Discussion Many researches had shown that cytochrome P450 enzymes could be induced or inhibited by some drugs. The changes of cytochrome P450 levels or activities could affect the drug concentration of blood, the pharmacokinetic process and biological medicinal properties (21). Europe and the United States require that drug screens and metabolic researches based on the cytochrome P450 system should contain new drugs evaluations (22). This methodology for pharmacokinetic research in new chemical drugs development was also required by the Chinese CFDA. The concomitant treatment of herbal supplements and synthetic drugs had become popular. Chinese herbal medicines contained various biologically active ingredients. As a result, the herb-drug interactions had become a common clinical problem. Some studies reported that the mechanisms underlying the interaction between herbal medicines and conventional drugs mainly involved induction or inhibition of the activities of metabolic enzymes and drug efflux proteins. Therefore, potential herb-drug interactions involving Chinese herbal medicines were worthy to study the cytochrome P450 system (23). For the first time, we systematically investigated the effects of morroniside on the activity of CYP1A2, CYP2B6 and CYP3A in rats. The results of the study revealed the morroniside caused a dose-dependent induction of CYP3A activity, but it had no effect on CYP1A2 and CYP2B6 (data not published). Furthermore, we had shown that the morroniside treatment increased CYP3A protein and mRNA expression in rats. In this research, the antibody we used was not specific enough to distinguish CYP3A1 and CYP3A2, which were two main CYP3A isoforms and shared an 89% sequence similarity (24).