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 In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Na Liu ◽  
Ping Chen ◽  
Xiaojun Du ◽  
Junxia Sun ◽  
Shasha Han
Keyword(s):  
Human Liver ◽  
Competitive Inhibition ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Inhibition Model ◽  
Dose Dependent

Abstract Background Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin. Methods The effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 μM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver–Burk plots to characterize the specific inhibition model and kinetic parameters. Results Obtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 μM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 μM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 μM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 μM− 1 and the Kinact value of 0.0515 min− 1. Conclusions The in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.

scholarly journals EVALUATION OF THE CYTOCHROME P450 INHIBITORY EFFECT OF THYME OLEORESIN FROM THYMUS VULGARIS L. - AN IN VITRO STUDY

2018 ◽  
Vol 11 (9) ◽  
pp. 149
Author(s):  
Adeline Persia R ◽  
Anitha Roy ◽  
Lakshmi T
Keyword(s):  
Cytochrome P450 ◽  
Potassium Phosphate ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Thymus Vulgaris ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Ic50 Value ◽  
Dose Dependent

Objective: The objective of this study was to evaluate the effect of thyme oleoresin on cytochrome P450 (CYP3A4) enzyme.Materials and Methods: The different concentrations of thyme (5–100 μg/ml) were examined for its inhibitory property toward cytochrome P450 isoform (CYP3A4). Thyme, potassium phosphate buffer, CYP450 reagent, and substrate 7-Benzyloxy-4-trifluoromethylcoumarin were added to a 96-well plate. The mixtures were preincubated for 20 min at room temperature. The fluorescent intensities of the products were measured by PerkinElmer Enspire fluorescence reader using an excitation and emission wavelength of 405 nm and 460 nm, respectively. Values are expressed as mean ± standard error mean (n=3). IC50 was calculated by plotting concentrations of thyme against the corresponding percent inhibition.Results: All the tested concentrations of thyme showed inhibitory effect against CYP3A4 in a dose-dependent manner. At 5 μg/ml, it showed a percentage inhibition of 1.82±0.61, whereas 100 μg/ml showed 66.05±0.16. The IC50 value of thyme for CYP3A4 inhibitory activity was found to be 39.14 μg/ml.Conclusion: This study proves that the inhibitory effect of thyme oleoresin on cytochrome P450. The inhibitory effects of thyme indicate the possibilities of herb-drug interaction if this extract is coadministered with prescribed drugs that are metabolized by CYP3A4.

The effect of d,l-4-hydroxypropranolol on the thyroxine to 3,5,3'-triiodothyronine conversion in rat renal and liver microsomes

1984 ◽  
Vol 105 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Preben Holme Jørgensen ◽  
lb Bo Lumholtz ◽  
Jens Faber ◽  
Carsten Kirkegaard ◽  
Kaj Siersbæk-Nielsen ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Liver Microsomes ◽  
Parent Drug ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Vitro Effect ◽  
Dose Dependent

Abstract. The in vitro effect of d,l-4-hydroxypropranolol, a major pharmacological active metabolite of the beta adrenoceptor blocking drug d,l-propranolol, on the thyroxine (T4) to 3,5,3'-triiodothyronine (T3) conversion has been studied using rat renal and liver microsomal fractions. The results showed, that primarily the metabolite, but also the parent drug inhibits the T3-production in a dose dependent manner. The potency, expressed as the 50% inhibition of the T3-production, was reached using 65 ± 12 (sd) μm d,l-4-OH-propranolol and 1000 ± 22 (sd) μm d,l-propranolol, respectively in both tissues. The efficacy of 4-OH-propranolol corresponded to a maximal inhibition of 86 ± 7% while it for d,l-propranolol corresponded to 58 ± 6% (P < 0.001). The beta adrenoceptor agonist isoprenaline itself did not effect the T4 to T3 conversion but considerably opposed the inhibitory effect of d,l-4-OH-propranolol but not of d,l-propranolol. The D-isomer form of propranolol, which is without beta receptor blocking activity inhibited the T3-production in the same degree as d,l-propranolol. Evaluation of the enzyme kinetic data suggested that 4-OH-propranolol caused a competitive inhibition of both T4 and DTT. It is concluded, that the metabolite d,l-4-OH-propranolol is a much more potent and efficacious inhibitor of the T4-5'-deiodination than d,l-propranolol.

scholarly journals Obestatin Modulates Ghrelin’s Effects on the Basal and Stimulated Testosterone Secretion by the Testis of Rat: an In Vitro Study

2017 ◽  
pp. 93-98
Author(s):  
T. AFSAR ◽  
S. JAHAN ◽  
S. RAZAK ◽  
A. ALMAJWAL ◽  
M. ABULMEATY ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Inhibitory Effect ◽  
Human Chorionic Gonadotrophin ◽  
Dependent Manner ◽  
Control Groups ◽  
Adult Rats ◽  
Testosterone Secretion ◽  
Functional Antagonism ◽  
Dose Dependent

The functional antagonism between obestatin and ghrelin in the testis is under investigation. We investigated the ability of obestatin to counteract the inhibitory effect of ghrelin on basal and stimulated testosterone (T) secretion in vitro. Testicular strips from adult rats were incubated with 10 ng/ml and 100 ng/ml of obestatin alone, ghrelin alone and obestatin + ghrelin. Obestatin modulation of stimulated T secretion was evaluated by incubation of testicular samples with 10 ng/ml and 100 ng/ml obestatin, ghrelin and obestatin + ghrelin in the absence and presence of 10 IU of human chorionic gonadotrophin (hCG). T concentrations in the hCG treated groups were significantly (P<0.0001) higher than those in the control groups. Obestatin caused a significant increase in basal T secretion in a dose-dependent manner; however, obestatin at the both 10 ng/ml and 100 ng/ml significantly (P<0.0001) increased hCG-stimulated T secretion. In contrast, ghrelin in a dose-dependent manner significantly (P<0.001) decreased both basal and hCG-induced T secretion by testicular slices. Obestatin opposed the inhibitory effect of ghrelin on T secretion under both basal and hCG-stimulated conditions at all doses tested. In conclusions, administration of obestatin was able to antagonize the inhibitory effect of ghrelin on testosterone secretion in vitro.

scholarly journals TAMARIND EXTRACT INHIBITS CYTOCHROME P450 (CYP3A4 ISOZYME) - AN IN VITRO STUDY

2018 ◽  
Vol 11 (7) ◽  
pp. 333
Author(s):  
Jagadish Rajkumaar R ◽  
Anitha Roy ◽  
Lakshmi T
Keyword(s):  
Room Temperature ◽  
Potassium Phosphate ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Fruit Pulp ◽  
Ic50 Value ◽  
Dose Dependent ◽  
Cytochrome P 450

Objective: The aim of the present study was to analyze the effect of the aqueous fruit pulp extract of Tamarindus indica L. (tamarind extract) on cytochrome P 450 isoform CYP3A4.Methods: Tamarind extract at different concentrations from 5 to 100 μg/ml was examined for its inhibitory property toward cytochrome P 450 isoform CYP3A4. The various concentrations of tamarind extract, potassium phosphate buffer, CYP450 reagent, and substrate 7-Benzyloxy-4- trifluoromethylcoumarin were added to a 96-well plate. The mixtures were preincubated for 20 min at room temperature. The reaction was started by a mixture of free constituted substrate and NADP+ and incubated at room temperature for 30–60 min. The reaction was stopped by Tris-HCl buffer, pH 10.5. The fluorescent intensities of the products were measured by PerkinElmer Enspire fluorescence reader using an excitation and emission wavelength of 405 nm and 460 nm, respectively. Inhibitory concentration (IC50) was calculated by plotting concentrations of tamarind extract against the corresponding percentage inhibition.Results: All the tested concentrations of extract except 5 μg/ml showed good inhibition against CYP3A4 in a dose-dependent manner. The IC50 value of tamarind for CYP3A4 inhibitory activity was found to be 27.89 μg/ml.Conclusion: T. indica aqueous fruit pulp extract exhibited an inhibitory effect on CYP34A, thereby indicating the possibilities of herb-drug interaction if these extracts are coadministered with the prescribed drugs that are metabolized by CYP3A4.

Immunomodulatory activities of whey fractions in efferent prefemoral lymph of sheep

1996 ◽  
Vol 63 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Chun W. Wong ◽  
Geoffrey O. Regester ◽  
Geoffrey L. Francis ◽  
Dennis L. Watson
Keyword(s):  
Immune Responses ◽  
Bovine Milk ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Milk Whey ◽  
Significant Difference ◽  
Lymphocyte Phenotypes ◽  
Dose Dependent

SummaryStudies on the immunomodulatory activities of ruminant milk and colostral whey fractions were undertaken. By comparing with boiled colostral whey in a preliminary experiment, a putative heat-labile immunostimulatory factor for antibody responses was found to be present in ovine colostral whey. Studies were then undertaken in sheep in which the efferent prefemoral lymphatic ducts were cannulated bilaterally, and immune responses in the node were measured following subcutaneous injection in the flank fold of whey protein preparations of various purities. A significant sustained decline of efferent lymphocyte output was observed following injection with autologous crude milk whey or colostral whey preparations, but no changes were observed in interferon-gamma levels in lymph plasma. Two bovine milk whey fractions (lactoperoxidase and lactoferrin) of high purity were compared in bilaterally cannulated sheep. A transient decline over the first 6 h was seen in the efferent lymphocyte output and lymph flow rate after injection of both fractions. A significant difference was seen between the two fractions in interferongamma levels in lymph at 6 h after injection. However, no significant changes in the proportion of the various efferent lymphocyte phenotypes were seen following either treatment. Whereas both fractions showed a significant inhibitory effect in a dose-dependent manner on the proliferative response of T lymphocytes, but not B lymphocytes, to mitogenic stimulation in vitro, no similar changes were seen following in vivo stimulation with these two fractions.

In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity

2021 ◽  
Vol 22 ◽  
Author(s):  
Liyan Wang ◽  
Tingting Zhao ◽  
Yunxiang Wang ◽  
Banglian Hu ◽  
Jianfei Tao ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Cyp3a Activity ◽  
Drug Drug Interaction ◽  
Inhibitory Potential

Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. Molecular docking simulation was performed to explore the potential structural alerts. Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min–1, 1.96 μM and 0.037 min–1, and 9.94 μM and 0.031 min–1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.

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