Analysis of Serum Pharmacochemistry of Hederagenin using UPLC-Q-TOF/MS

Sains Malaysiana 51(5)(2022): 1373-1383 http://doi.org/10.17576/jsm-2022-5105-09

ABSTRACT This study investigated the changes of plasma absorbed components in rats after oral administration of hederagenin. Serum pharmacochemistry analysis of hederagenin was carried out to understand the changes of its metabolic components in the body. Biological samples were collected and then the migration components of hederagenin-containing serum were established by UPLC/Q-TOF-MS technique. Possible metabolites were obtained for comprehensive analysis through relevant studies and the regulation of broken bonds in the molecular structure of hederagenin. At about 10.262 min, the molecular ion peak of the hederagenin of M/Z 471[M-H]- was detected in negative ion mode and the prototype product and its associated fragment ions could be detected only at 1, 3, 6, 9, 12, and 24 h after administration. Seventy-one signal peaks of potential metabolites were found in the drug serum. Based on the bond energy characteristics of molecular structure, 47 possible metabolite-related molecular ion peaks through decarboxylation, dehydration, demethylation or methyl shift, deoxygenation, ring opening, and unsaturated biformation were deduced, and signals of 35 metaboliterelated molecular ion peaks were identified. Hederagenin can metabolize many products in vivo. Important information about the metabolism of hederagenin, which is useful for fully understanding its mechanism of action, was provided in this study.

INTRODUCTION The concept of serum pharmacochemistry was first proposed by Hiroko Iwama in 1987. Serum pharmacochemistry refers to the qualitative and quantitative analysis of serum or plasma using modern analytical methods (Iwama et al. 1987) to study the chemical substances and their metabolic regularity in serum. The proposal of this concept has broken the traditional research method of traditional Chinese medicine and compound prescription. The chemical composition may change after passing through the digestive and intestinal flora. After hydrolysis, oxidation and reduction reactions, the bioactive ingredients are often absorbed into the blood, or loop-cracking, cyclization, deester, dehydrogenation, demethylation, hydrogenation, and other reactions occur under the action of intestinal enzymes, forming metabolites into the blood. Wang et al. (2008) found that there is a close relationship between plasma components, their concentrations and their pharmacological effects. This finding can also be observed in herbal medicines (Xiong et al. 2013; Yan et al. 2013). Therefore, it is necessary to have a comprehensive understanding of drug absorption and pharmacokinetic information in pharmacological studies. Hederagenin, (3β, 4α)-3,23-dihydroxy olean-12- ene-28-acid, molecular formula C30H48O4 , is a pentacyclic triterpenoid compound, widely distributed in a variety of medicinal plants, such as Hedera helix L., Dipsacus asper, Clematis, Pulsatilla, Honeysuckle, and Predictor. Previous studies have shown that hederagenin have anti-tumor (Lee et al. 2000), anti-depression (Zhou et al. 2010), antibacterial, anti-inflammatory (Kim et al. 2017), antiatherosclerosis (Lu et al. 2015), anti-diabetic (Kim et al. 1998) and other pharmacological effects and biological activities (Choi et al. 2005; Wu et al. 2017). Due to the characteristics of poor solubility and low bioavailability of hederagenin found in previous studies, there are relatively few studies on the activity of hederagenin at this stage, and the clinical application is also limited accordingly. However, in the early stage of our laboratory, it was found that hederagenin still has good lipid-lowering activity under the condition of low bioavailability.

For thousands of years, Traditional Chinese medicine (TCM) theories have guided and explained the clinical efficacy of TCM and its extracts. However, the basic application principle and mechanism of action of these TCM cannot be explained by modern science, which is difficult to be accepted internationally. Therefore, the focus of TCM research today is to explore the pharmacological action and mechanism of action (Wang et al. 2018). To solve the problem, hederagenin still has good activity under the condition of low bioavailability, our group aimed to identify the biologically active components absorbed in the plasma of rats after gavage of hederagenin using UPLC/QTOF-MS instructed by plasma pharmacochemical ideas.

A chemical database of serum pharmacochemistry of hederagenin was established, which will lay a theoretical basis for further reveal the pharmacological effect of hederagenin and its metabolic components.

Sains Malaysiana 51(5)(2022): 1373-1383 http://doi.org/10.17576/jsm-2022-5105-09