scholarly journals Galeon: A Biologically Active Molecule with In Silico Metabolite Prediction, In Vitro Metabolic Profiling in Rat Liver Microsomes, and In Silico Binding Mechanisms with CYP450 Isoforms

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5903
Author(s):  
A. F. M. Motiur Rahman ◽  
Wencui Yin ◽  
Adnan A. Kadi ◽  
Yurngdong Jahng
Keyword(s):  
Rat Liver ◽  
Metabolic Profiling ◽  
In Silico ◽  
Ion Trap ◽  
Liver Microsomes ◽  
Biologically Active ◽  
Rat Liver Microsomes ◽  
Active Site Residues ◽  
In Silico Docking

Galeon, a natural cyclic-diarylheptanoid (CDH), which was first isolated from Myrica gale L., is known to have potent cytotoxicity against A549 cell lines, anti-tubercular activity against Mycobacterium tuberculosis H37Rv, chemo-preventive potential, and moderate topoisomerase inhibitory activity. Here, in silico metabolism and toxicity prediction of galeon by CYP450, in vitro metabolic profiling study in rat liver microsomes (RLMs), and molecular interactions of galeon-CYP450 isoforms were performed. An in silico metabolic prediction study showed demethyl and mono-hydroxy galeon were the metabolites with the highest predictability. Among the predicted metabolites, mono-hydroxy galeon was found to have plausible toxicities such as skin sensitization, thyroid toxicity, chromosome damage, and carcinogenicity. An in vitro metabolism study of galeon, incubated in RLMs, revealed eighteen Phase-I metabolites, nine methoxylamine, and three glutathione conjugates. Identification of possible metabolites and confirmation of their structures were carried out using ion-trap tandem mass spectrometry. In silico docking analysis of galeon demonstrated significant interactions with active site residues of almost all CYP450 isoforms.

In Vitro Metabolic Profiling of Periplogenin in Rat Liver Microsomes and its Associated Enzyme-kinetic Evaluation

2020 ◽  
Vol 16 (5) ◽  
pp. 504-512
Author(s):  
Yingshu Feng ◽  
Jinyi Wan ◽  
Baoding Chen ◽  
Yuan Zhu ◽  
Caleb Kesse Firempong ◽  
...  
Keyword(s):  
Rat Liver ◽  
Metabolic Profiling ◽  
Biological Activities ◽  
Liver Microsomes ◽  
Internal Standard ◽  
Rat Liver Microsomes ◽  
Enzyme Kinetic ◽  
Kinetic Evaluation ◽  
Relative Standard

Background: Periplogenin, an active ingredient in Cortex Periplocae, is widely noted for its multiple biological activities; however, the metabolism of this compound has been scarcely investigated. The present report proposed the in vitro metabolic profiling and reaction pathways of periplogenin in rat liver microsomes. Method and Results: The metabolites of periplogenin in rat liver microsomes were analyzed. Two main metabolites, namely 14-hydroxy-3-oxo-14β-carda-4, 20 (22)-dienolide and 5, 14-dihydroxy-3-oxo-5β, 14β-card-20(22)-enolide were identified by HPLC-MSn, 1H-NMR and 13C-NMR. HPLC method was established for the simultaneous determination of periplogenin and its related metabolites (M0, M1 and M2), which was performed on Waters ODS column with a methanol-water solution (53:47, v/v) as mobile phase and descurainoside as an internal standard at 220 nm. The linearity ranges of M0, M1 and M2 were 0.64-820.51, 0.68-864.86 and 0.64-824.74 μM respectively with the regression coefficient (R2) above 0.9995. The limits of quantitation for these metabolites (M0, M1 and M2) were 0.18, 0.22 and 0.15 μM respectively. The developed method was also accurate (with relative errors of -3.6% to 3.2%) and precise (with relative standard deviations below 7.9%). The recoveries of the three analytes were above 85.7% with stability in the range of -2.4% to 3.6%. The enzyme-kinetic parameters of periplogenin including Vmax (6.08 ± 0.19 nmol/mg protein/min), Km (288.62 ± 14.54 μM) and Clint (21 ± 1.0 μL/min/mg protein) were calculated using nonlinear regression analysis. Conclusion: These findings significantly highlighted the metabolic pathways of periplogenin and also provided some reference data for future pharmacokinetic and pharmacodynamic studies.

In vitro metabolism in Sprague–Dawley rat liver microsomes of forsythoside A in different compositions of Shuang–Huang–Lian

Fitoterapia ◽  
2011 ◽  
Vol 82 (8) ◽  
pp. 1222-1230 ◽  
Author(s):  
Wei Zhou ◽  
Liu-qing Di ◽  
Jin-jun Shan ◽  
Xiao-lin Bi ◽  
Le-tian Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Sprague Dawley Rat

scholarly journals In Vitro Characterization of Borneol Metabolites by GC--MS Upon Incubation with Rat Liver Microsomes

2008 ◽  
Vol 46 (5) ◽  
pp. 419-423 ◽  
Author(s):  
R. Zhang ◽  
C.-h. Liu ◽  
T.-l. Huang ◽  
N.-s. Wang ◽  
S.-q. Mi
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
In Vitro Characterization

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

scholarly journals SYNTHESIS AND CHARACTERIZATION OF CYCLOHEXANE-1,3-DIONE DERIVATIVES AND THEIR IN SILICO AND IN VITRO STUDIES ON ANTIMICROBIAL AND BREAST CANCER ACTIVITY

2019 ◽  
pp. 311-320 ◽  
Author(s):  
RAJA CHINNAMANAYAKAR ◽  
EZHILARASI MR ◽  
PRABHA B ◽  
KULANDHAIVEL M
Keyword(s):  
Breast Cancer ◽  
Antimicrobial Activity ◽  
Anticancer Activity ◽  
Mtt Assay ◽  
In Silico ◽  
Biologically Active ◽  
Diffusion Method ◽  
Breast Adenocarcinoma ◽  
In Silico Docking

Objective: The objective of this study was to evaluate in silico and in vitro anticancer activity for synthesized cyclohexane-1,3-dione derivatives. Methods: The new series of cyclohexane-1,3-dione derivatives were synthesized based on the Michael addition reaction. Further, the structures of the synthesized compounds were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), and 13C NMR spectral data. Then, the in silico molecular docking studies were carried out using AutoDock tool version 1.5.6 and AutoDock version 4.2.5.1 docking program. The antimicrobial activity was carried out using the agar disk diffusion method, and the in vitro anticancer activity was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for the synthesized compound. Results: In silico docking study, compound 5c showed good binding score and binding interactions with selected bacterial proteins and breast cancer protein. Further, compound (5a-5h) was tested for their antimicrobial activity and compound 5c was only tested for anticancer activity (human breast adenocarcinoma 3,4-methylenedioxyamphetamine-MB-231 cell line). Compound 5c was found to be the most active one of all the tested compounds. In the MTT assay compound, 5c showed the LC50 value of 10.31±0.003 μg/ml. In antimicrobial activity, the minimum inhibitory concentration of compound 5c is 2.5 mg/ml. Conclusion: An efficient synthesis of biologically active cyclohexane-1, 3-dione derivatives has been developed.

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