Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine

Abstract

1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 μM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb-drug interactions, providing important information for predicting drug-induced hepatotoxicity.

Biologically active quinoline and quinazoline alkaloids part II

“…However, rutaecarpine, a related quinazoline alkaloid, decreased the primary rat hepatocyte viability, increased lactate dehydrogenase and ROS, reduced JC‐1, and caused cell stress and membrane damage. It inhibited the activities of cytochrome P450 enzymes (CYPs) in human liver microsomes, especially CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, which could lead to herb–drug interactions or result in hepatotoxicity …”

“…164,165 Furthmore, trigonoine B (195) (Figure 24) showed weak anti-HIV activity, preventing the cytopathic effects of HIV-1 IIIB in C8166 cells with an EC 50 value of 17.6 g/mL and TI value of 4.48, but no anti-HBV activity. 166 Meanwhile, waltheriones A (121) and C (122) ( Figure 16) showed significant effects in an in vitro anti-HIV cytoprotection assay at concentrations of 56.2 and 0.84 M and inhibition of HIV P24 formation of more than 50% at 1.7 and 0.95 M, respectively, while waltheriones B (196) and D (197) (Figure 24) were only weakly active or inactive. 167 Hepatitis C virus (HCV) infection is highly prevalent among global populations.…”

Effect of health foods on cytochrome P450-mediated drug metabolism

“…Silibinin has been reported to inhibit CYP2C9 and CYP3A4 through mechanism-based inhibition (MBI) [15]. It was recently reported that a metabolite of rutaecarpine, a principal constituent of Evodia rutaecarpa , strongly inhibits P450s [16], suggesting that health food-drug interactions could be caused by P450 inhibition through MBI.…”

Qualitative screening of absorbed indoloquinazoline alkaloids and their metabolites in rat plasma after the oral administration of Wu‐Zhu‐Yu decoction by high‐resolution mass spectrometry with multiple data mining algorithms

“…A considerable number of studies on TCM prescriptions have focused on metabolic research to discover the phytochemical constituents necessary for therapeutic efficacy, as growing awareness that TCM metabolism studies played as determinants in vivo . However, there was sparse data concerning metabolic studies of WZYD or Euodiae Fructus in vivo, except for a few reports that only investigated the metabolism of some alkaloids individually . Clinically, the prescription of WZYD possesses a much wider field of application than the herb Euodiae Fructus as well as the relative alkaloids.…”

“…Therefore, the study of in vivo metabolism of the prescription was of significance to help understand the pharmacological mechanism of the prescription. The previous studies concerned metabolism of evodiamine and its analogous alkaloids were all metabolism studies in vitro , while this is the first study that reported the plasma metabolism of evodiamine and its analogous alkaloids in vivo. Different to the previous in vitro studies and the in vivo studies with single administration, the study simulated the actual clinical treatment of the TCM formula with continuous administration.…”