Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice

Abstract

Oridonin, the major terpene found in Rabdosia rubescens, is widely used as dietary supplement or therapeutic drug, while the effects of oridonin on CYP450 were still unclear. The pregnane X receptor (PXR) is an important regulatory factor for major drug metabolism enzyme CYPs, and it has been reported to have species-specific differences. Therefore, this study has employed more reliable models PXR-humanized mouse to investigate the influence of oridonin on PXR and downstream metabolism enzyme. Eight-week-old male PXR-humanized mice were treated with oridonin by orally (0, 25, 50, 100, 200 mg/kg) for 15 d. The effects of oridonin on major downstream CYPs of PXR were examined at both the mRNA and enzyme activity levels by RT-PCR and HPLC-MS/MS. In general, there was no significant toxic reaction in liver of PXR-humanized mice. The mRNA expression of CYPs and cytochrome P450 oxidoreductase (POR) were increased with oridonin treatment in a dose-dependent manner. CYP2c and CYP3a family catalytic activity were increased significantly in two higher doses groups. These results indicate that oridonin induced the expression and activation of CYP2c and CYP3a family, which might contribute to potential drug-drug interactions and appear to be a risk when co-administered with other clinical drugs.

Direct cellular targets and anticancer mechanisms of the natural product oridonin

“…168 At very high concentrations, oridonin (100 and 200 mg/kg per day for 15 days) could enhance the expression of cytochrome P450 (CYP450) enzymes, such as CYP2c and CYP3a in pregnane X receptor (PXR)humanized mice, thereby potentially contributing to drug-drug interactions. 169 Furthermore, oridonin could also induce developmental abnormalities in zebrafish at 120 h postfertilization with a half maximal effective concentration (EC 50 ) of 411.94 mg/L. 170 In addition, due to its potent anti-inflammatory function, oridonin is considered to have immunosuppressive activity.…”

Oridonin: A Review of Its Pharmacology, Pharmacokinetics and Toxicity

“…Another similar study also indicated that 16 phase I and 2 phase II metabolites were detected after oral administration of oridonin in rats, and the main biotransformation pathways of oridonin were reduction, oxidation, dehydroxylation and glucuronic acid coupling ( Tian et al, 2015 ). In addition, the treatment of HepaRG cells with oridonin at concentration of 1, 5, 10, and 20 µM demonstrated that oridonin induced the mRNA and protein expression and enzyme activity of CYP450s, especially on the CYP3A4 and CYP2C9 ( Zhang Y. W. et al, 2018 ). Besides, studies have also shown that oridonin could induce the expression of human CYP3A4 mRNA and protein through pregnane X receptor-mediated (PXR) pathway.…”

“…On the other hand, some reports suggested that oridonin could induce the expression and activation of CYP2C and CYP3A family ( Zhang Y. W. et al, 2018 ), and appeared to be a potential risk to herb-drug interactions as a result of its induction effects on drug processing genes expression and activation ( Zhang Y.-w. et al, 2014 ). Therefore, these reports suggested that we should pay attention to the safety issues caused by the combination of oridonin in clinical practice.…”

Molecular epidemiology; New but impressive

“…Examination of the relationship between polymorphism of CYP1A1 gene and tobacco-related cancers in the upper aerodigestive tract or relationship between a special variant of CYP and increases the risk of breast and head and neck cancer especially in people with inherited glutathione-s-transferase (GST) M1 ( 9 - 10 ). Also, other approach is XRCC1 variant alleles that display inferior base excision repair capacities that can be related to greater risk of oral and pharyngeal cancer ( 11 ).…”