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Bone Regeneration Effect of Cassia occidentalis Linn. Extract and Its Isolated Compounds
Published in Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay, Phytochemistry of Plants of Genus Cassia, 2021
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay
In a widely used model of iatrogenic osteoporosis obtained by the administration of a corticosteroid, methylprednisolone (MP), CSE (250 mg/kg) and CBE (100 mg/kg) mitigated MP-induced bone loss and strength by osteogenic as well as anti-catabolic actions. Even at a 2.5-fold lesser dose than CSE, the osteogenic effect of CBE was significantly greater than CSE. Both CSE and CBE mitigated MP-induced loss of body weight and electrolyte imbalances with later being more effective (Pal et al., 2019). Through an LC-MS/MS method, apigenin, isovitexin, luteolin, emodin and trihydroxyflavone were detected in adult rat plasma after an oral administration of CSE (500 mg/kg) (Pal et al., 2019). These compounds were stable in simulated gastric and intestinal fluids but were metabolized in rat liver microsomes. The development of bioanalytical methods for pharmacokinetics and in vitro stability studies of osteogenic compounds will be useful for the phase 1 clinical trial.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Benzoates and arylacetates are the prototype substrates for characterization of the enzymes catalyzing amino acid conjugation of the carboxylic acid moieties on xenobiotics. Kidney and liver mitochrondria are known sites of localization of the amino acid conjugation enzymes for these substrates. In mammals, there are at least two forms of CoA ligases for benzoic acid as substrate; the two forms are distinguished by differential specificity for salicylate conjugation. There are also at least two N-acyltransferases, one with benzyl CoA as the preferred substrate and one with arylacetyl CoA as the preferred substrate. Additional forms of CoA ligase and N-acyltransferase are specific for bile acid conjugation. Liver microsomes have high activities of these enzymes.
Alcohol
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Hepatic microsomes are responsible for a large number of metabolic functions. On theoretical grounds one can postulate that several of these functions (which have not as yet been extensively studied) will be found to be affected by either acute or chronic ethanol consumption. One can now anticipate a number of reports, such as the prevention of hyperbilirubinemia of the newborn by ethanol,147 attributed to induction of microsomal uridine - diphosphate-glucuronyl transferase.148 The possible role of microsomal changes (induced by ethanol consumption) in the development of ethanol dependence is particularly intriguing, as discussed subsequently.
Investigation on the in vitro metabolism of bicyclol using liver microsomes, hepatocytes and human recombinant cytochrome P450 enzymes
Published in Xenobiotica, 2023
Fengping Chen, Haizhu Zou, Ping Zhang, Yuqi Yan
Liver microsomes has been demonstrated the most widely used tool to investigate drug metabolism. In this study, the metabolites were generated by incubating liver microsomes with bicyclol and the samples were analysed by LC-MS. The retention times, elemental compositions, theoretical and measured masses and mass errors of the metabolites were summarised in Table 1. Figure 2 showed the extracted ion chromatograms of bicyclol-associated metabolites from RLM, CLM and HLM. Totally, ten phase I metabolites were detected and tentatively identified. Among these metabolites M6, M8, and M9 were the predominant metabolites in RLM. In CLM, M10 was also the major metabolite in addition to M6, M8 and M9. M4 and M7 were monkey-specific. In HLM, four minor metabolites (M6, M8, M9 and M10) were detected.
Metabolic profiling in liver microsomes and mice of E28, a potent FLT3 inhibitor
Published in Xenobiotica, 2022
Yan Tan, Xiandeng Li, Minghai Tang, Huan Wang, Yong Chen, Haoyu Ye, Jiajia Zhao, Rui Wu, Panhong Wei, Leilei Du, Li Wan
E28 went through diverse degrees of metabolism in different liver microsomes. The metabolic rate was slow in rat liver microsomes, while moderate in human, mouse, dog and monkey liver microsomes. Specific results are shown in Table 1. Linear regression was performed between the natural logarithm of the remaining percentage of E28 and incubation time, and the incubation curves of E28 in various liver microsomes were shown in Figure 1(a). The in vitro metabolic half-lives T1/2 of E28 metabolised in human, rat, mouse, dog, and monkey liver microsomes were 14.56, 101.91, 15.37, 20.75, 22.35 min, respectively; the intrinsic clearances were 95.20, 13.60, 90.20, 66.80, and 62.00 mL/min/mg protein, respectively. The results indicated that there were species differences in metabolic stability, as E28 displayed low clearance in rat liver microsomes while moderate clearance in other species, and the experimental parameters of mice have closer value to humans compared to other tested species. Based on these data combined with the results of in vitro metabolite study, the mouse may be temporarily selected as an animal model for the study of E28 pharmacokinetics and metabolism in human. In order to justify the reliability of animal models, the further studies in vitro utilising hepatocytes will be added for verification in the later stage.
Agrimoniin inhibits the activity of CYP1A2, 2D6, and 3A4 in human liver microsomes
Published in Xenobiotica, 2021
Yanqing Zhou, Qian Xian, Haimin Wei, Jin Zhou, Shengjian Li, Junwei Yang, Xuedong Zhou, Yamei Li
Even though microsomes are the main means of the investigation of CYP450 enzyme activity, CYP450 enzymes have also been illustrated to exist in the intestinal and are involved in the metabolism of various drugs (Thelen and Dressman 2009). Therefore, the effect of agrimoniin on the activity of CYP450 enzymes needs to be validated in the intestinal, which can give more guidance for the medication of agrimoniin and Agrimonia pilosa Ledeb. However, the lack of in vivo investigations is another limitation of the present study. Currently, there are few commercial products containing pure agrimoniin and its herbal content is low. Previously, Olennikov et al. (2014) found that the concentration of agrimoniin in the extraction of Potentilla anserina L. herb (Rosaceae) is closely related to the extract type (Olennikov et al. 2014). The in vivo pharmacokinetics of agrimoniin is also a crucial factor that determines the effective concentration of agrimoniin. Therefore, further in vivo pharmacokinetic study should be performed to evaluate the potential of the interactions between agrimoniin and CYP1A2-, CYP2D6-, and CYP3A4-metabolised drugs.