scholarly journals Bioactivity of Curcumin on the Cytochrome P450 Enzymes of the Steroidogenic Pathway

2019 ◽  
Vol 20 (18) ◽  
pp. 4606 ◽  
Author(s):  
Rodríguez Castaño ◽  
Parween ◽  
Pandey
Keyword(s):  
Cytochrome P450 ◽  
Active Sites ◽  
Curcuma Longa ◽  
Docking Studies ◽  
Steroid Metabolism ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Lead Compounds ◽  
Anti Cancer ◽  
Mild Reduction

Turmeric, a popular ingredient in the cuisine of many Asian countries, comes from the roots of the Curcuma longa and is known for its use in Chinese and Ayurvedic medicine. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have potent wound healing, anti-inflammatory, and anti-carcinogenic activities. While curcuminoids have been studied for many years, not much is known about their effects on steroid metabolism. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the effect of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. When using 10 µg/ml of curcuminoids, both the 17α-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, only a mild reduction in CYP21A2 activity was observed. Furthermore, CYP19A1 activity was also reduced up to ~20% of control when using 1–100 µg/ml of curcuminoids in a dose-dependent manner. Molecular docking studies confirmed that curcumin could dock onto the active sites of CYP17A1, CYP19A1, as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies suggest that curcuminoids may cause inhibition of steroid metabolism, especially at higher dosages. Also, the recent popularity of turmeric powder as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. The molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

scholarly journals Bioactivity of curcumin on the cytochrome P450 enzymes of the steroidogenic pathway

2019 ◽  
Author(s):  
Patricia Rodríguez Castaño ◽  
Shaheena Parween ◽  
Amit V Pandey
Keyword(s):  
Cytochrome P450 ◽  
Active Sites ◽  
Curcuma Longa ◽  
Docking Studies ◽  
Steroid Metabolism ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Lead Compounds ◽  
Anti Cancer ◽  
Mild Reduction

AbstractTurmeric, a popular ingredient in the cuisine of many Asian countries, comes from the roots of theCurcuma longaand is known for its use in Chinese and Ayurvedic medicine. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have potent wound healing, anti-inflammatory, and anti-carcinogenic activities. While curcuminoids have been studied for many years, not much is known about their effects on steroid metabolism. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the effect of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. When using 10 µg/ml of curcuminoids, both the 17α-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, only a mild reduction in CYP21A2 activity was observed. Furthermore, CYP19A1 activity was also reduced up to ~20% of control when using 1-100 µg/ml of curcuminoids in a dose-dependent manner. Molecular docking studies confirmed that curcumin could dock into the active sites of CYP17A1, CYP19A1 as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies suggest that curcuminoids may cause inhibition of steroid metabolism, especially at higher dosages. Also, the recent popularity of turmeric powder as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. Molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

scholarly journals Bioactivity of Curcumin on the Cytochrome P450 Enzymes of the Steroidogenic Pathway

2019 ◽  
Author(s):  
Patricia Rodríguez Castaño ◽  
Shaheena Parween ◽  
Amit V Pandey
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cytochrome P450 ◽  
Active Sites ◽  
Curcuma Longa ◽  
Steroid Metabolism ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Lead Discovery ◽  
Vitro Assay

Turmeric is a popular ingredient in the cuisine of many Asian countries. Turmeric is known for its use in Chinese and Ayurvedic medicine and comes from the roots of the Curcuma longa. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcumin has potent anti-inflammatory and anti-carcinogenic activities. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the bioactivity of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. Curcuminoids were extracted from turmeric with organic solvents. We conducted a cell-based assay for CYP17A1 and CYP21A2 activities using human adrenal cell line NCI-H295R. 3H-pregnenolone was used for CYP17A1 assays, and 3H-17alpha-hydroxyprogesterone was used as a substrate for CYP21A2. Curcuminoids were added at different concentrations and incubated for 24h. Steroids were separated by thin layer chromatography and analyzed by phosphorimager analysis. For CYP19A1 activity, an in vitro assay using endoplasmic reticulum from JEG3 were used with 3H-androstenedione as the substrate. Curcuminoids were incubated for 1h, and the formation of 3H-water from the androstenedione breakdown was measured by scintillation counting. When using 10 µg/ml of curcuminoids, both the 17-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, CYP21A2 activity was only reduced to ~50% control. Furthermore, CYP19A1 activity was reduced to ~20% of control when using 1-100 µg/ml of curcuminoids in a dose-dependent manner. No effect on the activity of 5alpha reductase for the conversion of androstenedione to androstanedione was observed. Molecular docking studies confirmed that curcumin could dock into the active sites of CYP17A1, CYP19A1 as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies show that curcuminoids may potentially cause inhibition of steroid metabolism, especially at higher dosages. The activities of CYP17A1 and CYP19A1 were inhibited by curcuminoids, which indicate potential anti-carcinogenic effects in case of prostate cancer as well as breast cancer, which can be targeted by inhibition of steroidogenesis. Also, the recent popularity of turmeric powder/curcumin as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. Curcuminoids present in curcumin may affect activities of multiple steroid metabolizing cytochrome P450 enzymes. Computational docking suggests curcumin binds into the active sites of steroid metabolizing P450s and may serve as a model for lead discovery. Molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

scholarly journals In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qun Zhang ◽  
Zengqiang Qu ◽  
Yanqing Zhou ◽  
Jin Zhou ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Drug Drug Interaction ◽  
Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

scholarly journals Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Debendranath Dey ◽  
Sunetra Chaskar ◽  
Nitin Athavale ◽  
Deepa Chitre
Keyword(s):  
Cytochrome P450 ◽  
Radioligand Binding ◽  
Curcuma Longa ◽  
Raw 264.7 Cells ◽  
Cytochrome P450 Enzyme ◽  
Sprague Dawley ◽  
Cytochrome P450 Enzymes ◽  
Boswellia Serrata ◽  
Cell Counts ◽  
Anti Inflammatory

Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation ofWithania somnifera, Boswellia serrata, Zingiber officinale,andCurcuma longa,inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.

scholarly journals Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

2020 ◽  
Vol 48 (5) ◽  
pp. 326-336 ◽  
Author(s):  
Yifan Bao ◽  
Pei Wang ◽  
Xueyan Shao ◽  
Junjie Zhu ◽  
Jingcheng Xiao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Injury ◽  
Mouse Liver ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Age Dependent

scholarly journals MOLECULAR DOCKING STUDIES OF CURCUMA LONGA AND ALOE VERA FOR THEIR POTENTIAL ANTICANCER EFFECTS

2018 ◽  
Vol 11 (4) ◽  
pp. 314 ◽  
Author(s):  
Parul Tripathi ◽  
Saad Sabir Siddiqui ◽  
Anju Sharma ◽  
Parul Johri ◽  
Aditi Singh
Keyword(s):  
Topoisomerase I ◽  
Active Sites ◽  
Rational Design ◽  
Curcuma Longa ◽  
Aloe Vera ◽  
Initial Step ◽  
Docking Study ◽  
Single Copy ◽  
Docking Studies ◽  
Anticancer Effects

 Objective: In this paper, docking study is presented to use these phytocompounds for their prospective role in various types of cancers.Methods: A group of the different set of phytocompounds (aloesin, barbaloin, curcumin, and emodin) were taken and docked into the active sites of Topoisomerase I, a 91-kDa monomer (having 765 amino acids), is encoded by a single copy gene (Top 1) located on chromosome 20q12–13.2 using Autodock4 Software. The docking studies of the selected proteins were also docked to study the anticancerous property of the selected phytocompounds.Result: These studies were based on binding energy, docking energy and other relevant scores that revealed emodin could be the potential lead molecule for the inhibition of signal potent for different types of cancer. Furthermore, the important residues for potential drug target were identified.Conclusion: This paper is an initial step toward a rational design of novel selective and potent phytocompounds inhibitors for the treatment of deadly disease cancer.

scholarly journals MEMS directed evolution of two cytochrome P450 enzymes revealing distinct active-sites for convergent functions

2020 ◽  
Author(s):  
Li Ma ◽  
Fengwei Li ◽  
Xingwang Zhang ◽  
Hui Chen ◽  
Qian Huang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Directed Evolution ◽  
Active Sites ◽  
Enzyme Engineering ◽  
Proof Of Concept ◽  
Cytochrome P450 Enzymes ◽  
Natural Evolution ◽  
One Pot ◽  
P450 Bm3 ◽  
Protein Enzyme

AbstractDirected evolution (DE) inspired by natural evolution (NE) has been achieving tremendous successes in protein/enzyme engineering. However, the conventional ‘one-protein-for-one-task’ DE cannot match the ‘multi-proteins-for-multi-tasks’ NE in terms of screening throughput and efficiency, thus often failing to meet the fast-growing demands for biocatalysts with desired properties. In this study, we design a novel ‘multi-enzyme-for-multi-substrate’ (MEMS) DE model and establish the proof-of-concept by running a NE-mimicking and higher-throughput screening on the basis of ‘two-P450s-against-seven-substrates’ (2P×7S) in one pot. With the significantly improved throughput and hit-rate, we witness a series of convergent evolution events of the two archetypal cytochrome P450 enzymes (P450 BM3 and P450cam) in laboratory. Further structural analysis of the two functionally convergent P450 variants provide important insights into how distinct active-sites can reach a common catalytic goal.

scholarly journals Cytochrome P450 and P-gp Mediated Herb-Drug Interactions and Molecular Docking Studies of Garcinol

Membranes ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 992
Author(s):  
Lavanya Bolla ◽  
Pratima Srivastava ◽  
Velayutham Ravichandiran ◽  
Satheesh Kumar Nanjappan
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Drug Interactions ◽  
Active Sites ◽  
Docking Studies ◽  
Rat Liver Microsomes ◽  
Garcinia Cambogia ◽  
Molecular Docking Studies ◽  
Garcinia Indica

Garcinol is an active constituent of Garcinia indica and Garcinia cambogia. Recent studies have proven that garcinol has anti-inflammatory, anti-cancer, and anti-oxidant activities. The objective of this study was to evaluate the inhibitory effects of garcinol on the activities of the drug metabolizing cytochrome P450 (CYP) isozymes to predict potential herb-drug interactions with co-administered drugs. Garcinol was incubated with a mixture of rat liver microsomes and eight CYP probe substrate cocktail under optimized incubation conditions and the samples were analyzed using a validated method on LC-MS/MS. Garcinol showed strong inhibition with IC50 values of CYP1A2 (7.6 µM), CYP2C9 (8.0 µM), CYP2B6 (2.1 µM), CYP2D6 (9.5 µM), and CYP3A4 (5.1 µM), respectively, and moderate inhibition towards CYP2C19 (16.4 µM) and CYP2E1 (19.0 µM). Molecular docking studies were performed on garcinol against the active sites of CYP2B6 and CYP3A4 proteins. These results further confirmed that the inhibitory activity of garcinol occurred by occupying the active sites of these human CYPs and by making favorable interactions with its key residues. In-vivo CYP inhibition studies were carried out in Sprague-Dawley rats. These results suggest garcinol may cause herb-drug interactions, mediated by inhibition of CYPs involved in drug metabolism in-vivo by altering the pharmacokinetic parameters like AUC and Cmax in a clinically significant manner. Garcinol was found to upregulate the expression and activity of P-gp in western blotting study and P-gp inhibition study in-vivo. These findings give a clear understanding to predict potential herb-drug/drug-drug interactions of garcinol for safe clinical use in future.

Inhibitory Effects of Garcinia cambogia Extract on CYP2B6 Enzyme Activity

Planta Medica ◽  
2017 ◽  
Vol 83 (11) ◽  
pp. 895-900 ◽  
Author(s):  
Jun Yu ◽  
Min Choi ◽  
Jong Park ◽  
Shaheed Rehman ◽  
Katsunori Nakamura ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Enzyme Activities ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzyme ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Garcinia Cambogia ◽  
P450 Enzyme

AbstractThis study assessed the inhibitory effects of Garcinia cambogia extract on the cytochrome P450 enzymes in vitro. G. cambogia extract was incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes and recombinant CYP2B6 isozyme, and the formation of the marker metabolites was measured to investigate the inhibitory potential on cytochrome P450 enzyme activities. The results showed that G. cambogia extract has significant inhibitory effects on CYP2B6 activity in a concentration-dependent manner. Furthermore, the inhibition was potentiated following preincubation with NADPH, indicating that G. cambogia extract is a time-dependent inhibitor of CYP2B6. Meanwhile, hydroxycitric acid, the major bioactive ingredient of G. cambogia extract, did not exhibit significant inhibition effects on cytochrome P450 enzyme activities. G. cambogia extract could modulate the pharmacokinetics of CYP2B6 substrate drugs and lead to interactions with those drugs. Therefore, caution may be required with respect to concomitant intake of dietary supplements containing G. cambogia extract with CYP2B6 substrates.

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