scholarly journals Impact of Panax ginseng and Ginkgo biloba extracts on expression level of transcriptional factors and xenobiotic-metabolizing cytochrome P450 enzymes

2016 ◽  
Vol 62 (1) ◽  
pp. 42-54 ◽  
Author(s):  
Anna Bogacz ◽  
Monika Karasiewicz ◽  
Karolina Dziekan ◽  
Danuta Procyk ◽  
Małgorzata Górska-Paukszta ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Panax Ginseng ◽  
Ginkgo Biloba ◽  
Mrna Level ◽  
Transcriptional Factors ◽  
Expression Level ◽  
Herbal Remedies ◽  
Cytochrome P450 Enzymes ◽  
Ginseng Extract ◽  
Cyp Enzymes

Summary Introduction: Despite widespread use of Panax ginseng and Ginkgo biloba, the data on the safety as well as herb-drug interactions are very limited. Therefore, we postulate that P. ginseng and G. biloba may modulate the activity and content of cytochrome P450 isozymes involved in the biotransformation of diverse xenobiotic substances. Objective: The aim of our study was to determine the influence of herbal remedies on the expression level of CYP enzymes and transcriptional factors. Methods: Male Wistar rats were given standardized Panax ginseng (30 mg/kg p.o.) or standardized Ginkgo biloba (200 mg/kg p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by realtime PCR method. Results: Our results showed a decrease of CYP3A1 (homologue to human CYP3A4) mRNA level after P. ginseng extract treatment. The CYP2C6 (homologue to human CYP2C9) expression was also reduced. Additionally, after 10 days of the treatment with P. ginseng an increase of CYP1A1 (homologue to human CYP1A1) and CYP1A2 (homologue to human CYP1A2) expression was observed. Moreover, G. biloba extract also caused an increase of expression level for CYP1A1, CYP2C6, CYP3A1 and CYP3A2. Conclusion: Our findings suggest that herbal extracts can modulate the expression of transcriptional factors and CYP enzymes involved in xenobiotic metabolism and chemical carcinogenesis.

Modulatory Effects of Korean Red Ginseng Extract (Panax ginseng C.A. Meyer) on Cytochrome P450 after Oral Administration to Mice for 14 Days

2012 ◽  
Vol 22 (8) ◽  
pp. 991-998 ◽  
Author(s):  
Hee-Yeon Kim ◽  
Woong-Shik Nam ◽  
Seong-Hee Kim ◽  
Hye-Ryang Jang ◽  
Mi-Kyoung Lee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Oral Administration ◽  
Panax Ginseng ◽  
Red Ginseng ◽  
Korean Red Ginseng ◽  
Ginseng Extract

scholarly journals Molecular Cloning and Identification of NADPH Cytochrome P450 Reductase from Panax ginseng

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6654
Author(s):  
Xian Zou ◽  
Yue Zhang ◽  
Xu Zeng ◽  
Tuo Liu ◽  
Gui Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Panax Ginseng ◽  
Pcr Analysis ◽  
Cytochrome P450 Reductase ◽  
Cytochrome P450 Enzymes ◽  
Phylogenetic Tree Analysis ◽  
Nadph Cytochrome ◽  
P450 Reductase ◽  
Meja Treatment ◽  
Nadph Cytochrome P450 Reductase

Ginseng (Panax ginseng C.A. Mey.) is a precious Chinese traditional medicine, for which ginsenosides are the most important medicinal ingredients. Cytochrome P450 enzymes (CYP450) and their primary redox molecular companion NADPH cytochrome P450 reductase (CPR) play a key role in ginsenoside biosynthesis pathway. However, systematic studies of CPR genes in ginseng have not been reported. Numerous studies on ginsenoside synthesis biology still use Arabidopsis CPR (AtCPR1) as a reductase. In this study, we isolated two CPR genes (PgCPR1, PgCPR2) from ginseng adventitious roots. Phylogenetic tree analysis showed that both PgCPR1 and PgCPR2 are grouped in classⅡ of dicotyledonous CPR. Enzyme experiments showed that recombinant proteins PgCPR1, PgCPR2 and AtCPR1 can reduce cytochrome c and ferricyanide with NADPH as the electron donor, and PgCPR1 had the highest enzymatic activities. Quantitative real-time PCR analysis showed that PgCPR1 and PgCPR2 transcripts were detected in all examined tissues of Panax ginseng and both showed higher expression in stem and main root. Expression levels of the PgCPR1 and PgCPR2s were both induced after a methyl jasmonate (MeJA) treatment and its pattern matched with ginsenoside accumulation. The present investigation suggested PgCPR1 and PgCPR2 are associated with the biosynthesis of ginsenoside. This report will assist in future CPR family studies and ultimately improving ginsenoside production through transgenic engineering and synthetic biology.

scholarly journals Cytochrome P450 enzymes: understanding the biochemical hieroglyphs

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 178 ◽  
Author(s):  
John T. Groves
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Reactive Intermediates ◽  
Heme Iron ◽  
Cytochrome P450 Enzymes ◽  
Steroid Biosynthesis ◽  
Reaction Cycle ◽  
Cyp Enzymes ◽  
Protein Architecture ◽  
Recent Advances

Cytochrome P450 (CYP) enzymes are the primary proteins of drug metabolism and steroid biosynthesis. These crucial proteins have long been known to harbor a cysteine thiolate bound to the heme iron. Recent advances in the field have illuminated the nature of reactive intermediates in the reaction cycle. Similar intermediates have been observed and characterized in novel heme-thiolate proteins of fungal origin. Insights from these discoveries have begun to solve the riddle of how enzyme biocatalyst design can afford a protein that can transform substrates that are more difficult to oxidize than the surrounding protein architecture.

Cytochrome P450 enzymes: a review on drug metabolizing enzyme inhibition studies in drug discovery and development

Bioanalysis ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 1355-1378
Author(s):  
Siva Nageswara Rao Gajula ◽  
Megha Sajakumar Pillai ◽  
Gananadhamu Samanthula ◽  
Rajesh Sonti
Keyword(s):  
Cytochrome P450 ◽  
Drug Discovery ◽  
Enzyme Inhibition ◽  
In Vitro Study ◽  
Cytochrome P450 Enzymes ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Cyp Enzymes ◽  
Cyp Inhibition

Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

scholarly journals The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

2020 ◽  
Vol 72 (6) ◽  
pp. 1685-1694 ◽  
Author(s):  
Przemysław J. Danek ◽  
Jacek Wójcikowski ◽  
Władysława A. Daniel
Keyword(s):  
Cytochrome P450 ◽  
Combined Therapy ◽  
Liver Microsomes ◽  
Atypical Neuroleptics ◽  
Cytochrome P450 Enzymes ◽  
Cyp Enzymes ◽  
Human Cytochrome ◽  
Competitive Mechanism ◽  
Mixed Mechanism

Abstract Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

Use of Cocktail Probe Drugs for Indexing Cytochrome P450 Enzymes in Clinical Pharmacology Studies – Review of Case Studies

2019 ◽  
Vol 13 (1) ◽  
pp. 3-18 ◽  
Author(s):  
Poonam Giri ◽  
Harilal Patel ◽  
Nuggehally R. Srinivas
Keyword(s):  
Clinical Pharmacology ◽  
Cytochrome P450 ◽  
Case Studies ◽  
Data Interpretation ◽  
Multiple Time ◽  
Cytochrome P450 Enzymes ◽  
Time Duration ◽  
Cyp Enzymes ◽  
Multiple Time Points ◽  
Cocktail Approach

Background: The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a cornerstone in clinical pharmacology studies. The first report of the famous “Pittsburg cocktail” has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug. Objective: The key objectives were: 1) To collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) To introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) To provide some futuristic views on the use of cocktail in drug discovery and development. Method: The review was compiled after consultation with databases such as PubMed (NCBI database) and Google scholar to source various published literature on cocktail approaches in drug development. Results: In the reviewed case studies, CYP indexing was achieved using a single time point (differing for specific CYP enzyme) plasma determination of the metabolite to parent ratio for all CYP enzymes with the exception of CYP3A4/5, where multiple time points were required for exposure measurement of midazolam and its metabolite. Likewise, a single void of urine, for a specific time duration, has been utilized for the recovery measurements of parent and metabolite for CYP indexing purposes. Conclusion: The review provides a comprehensive list of various types of cocktail approaches and discusses some key considerations including the evolution of the cocktail approaches over time, perspectives and futuristic views for the use of probe drugs to aid the execution of clinical pharmacology studies and data interpretation.

Ginkgo biloba extract attenuates warfarin-mediated anticoagulation through induction of hepatic cytochrome P450 enzymes by bilobalide in mice

Phytomedicine ◽  
2012 ◽  
Vol 19 (2) ◽  
pp. 177-182 ◽  
Author(s):  
Yuko Taki ◽  
Kaori Yokotani ◽  
Shizuo Yamada ◽  
Kazumasa Shinozuka ◽  
Yoko Kubota ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Ginkgo Biloba ◽  
Ginkgo Biloba Extract ◽  
Cytochrome P450 Enzymes ◽  
Hepatic Cytochrome

scholarly journals A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Li ◽  
Ying-Yuan Lu ◽  
Jun Jia ◽  
Meng Fang ◽  
Lin Zhao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Evaluation System ◽  
Human Fibroblasts ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Cyp Enzymes ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Toxicity Of Drugs

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS–SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

scholarly journals Investigations on hepatic and intestinal drug-metabolizing cytochrome P450 enzymes in wild boar compared to domestic swine

2019 ◽  
Vol 66 (1) ◽  
Author(s):  
Ádám Kurucz ◽  
Kata Orbán ◽  
Máté Mackei ◽  
Hedvig Fébel ◽  
Zsuzsanna Neogrády ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Wild Boar ◽  
Specific Activity ◽  
Environmental Pollutants ◽  
Hepatic Metabolism ◽  
Bioactive Molecules ◽  
Cytochrome P450 Enzymes ◽  
Wild Boars ◽  
Cyp Enzymes ◽  
Domestic Swine

AbstractDrug-metabolizing cytochrome P450 (CYP) enzymes are especially important in wild animals as they are directly exposed to environmental pollutants and bioactive molecules of plants. Our main goal was to monitor the activity of certain CYP enzymes in wild boar compared to domestic swine, and to assess various modulatory factors of xenobiotic biotransformation in wild boar. Liver and intestinal mucosa (duodenum, jejunum, ileum, caecum) samples were collected from 49 hunted free-range wild boars and 15 wild boar fetuses; domestic pig samples (n = 40) were gained from a slaughter house. Specific activity of CYP1A2, CYP2C9, and CYP3A4 enzymes was assessed by luminometric assays. The activity of hepatic CYP1A2 and CYP3A4 enzymes was significantly higher in wild boars than in domestic pigs, while CYP2C9-mediated hepatic metabolism was significantly less intense in wild boars than in pigs. Certain modulatory factors (sex, sexual maturation, and season) were also confirmed in wild boars. The activity of all investigated intestinal CYP enzymes remained under detection level in each gut section in both species. Hepatic CYP2C9 and CYP3A4 enzymes were measurable in wild boar fetuses, but their activity was remarkably lower than in adults. The described interspecies differences might be explained with the altered exposure of wild and domesticated animals to specific CYP modulators. As CYP enzymes in wild boars can be highly influenced by environmental pollutants, following further studies, they may serve as ecotoxicological markers of agricultural or industrial toxicants. Investigating CYP-related drug metabolism in wildlife species can clarify some toxicokinetic interactions, thus having huge importance in the production of safe game meat.

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