scholarly journals Inhibition of Human Cytochrome P450 Metabolism by Blended Herbal Products and Vitamins

2011 ◽  
Vol 14 (1) ◽  
pp. 1 ◽  
Author(s):  
Teresa W Tam ◽  
Humayoun Akhtar ◽  
John Thor Arnason ◽  
Kosta Cvijovic ◽  
Heather Boon ◽  
...  
Keyword(s):  
Adverse Event ◽  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Drug Disposition ◽  
Natural Health Products ◽  
Carotene Content ◽  
Herbal Products ◽  
Cytochrome P450 Activity ◽  
Health Products

Purpose. The use of supplements as herbal and micronutrient natural health products with conventional health products has become increasingly popular. It has been reported that some herbal products can inhibit the activity of cytochrome P450-mediated metabolism and drug disposition. This study was designed to investigate a case report of a severe adverse event to determine the potential interactions of femMED, Thyrosense and vitamins on cytochrome P450-mediated drug metabolism. Methods. The effect of extracts from these commercially available herbal formulations, trans-ß-carotene, multivitamins, and vitamin D3 supplements on cytochrome P450-mediated drug metabolism of marker substrates was determined in vitro. Results. The blended herbal products femMED and Thyrosense had a high potential to affect the safety and efficacy of many health products. Some vitamin and trans-β-carotene containing products also have the potential to affect drug disposition. The ß-carotene content of various products was analyzed and significant discrepancies were found among them and between values indicated on product labels. Product extracts also exhibited a low to moderate capacity to inhibit cytochrome P450 2C9, 2C19 and 3A4-mediated metabolism. Conclusions. The findings of this study suggest that these herbal products and most vitamin products may have an inhibitory effect on cytochrome P450 activity that could contribute to development of an adverse event. Further work is warranted to determine how supplementation with these products may affect drug metabolism in an in vivo context.

In vitro activity of uva-ursi against cytochrome P450 isoenzymes and P-glycoproteinThis article is one of a selection of papers published in this special issue (part 2 of 2) on the Safety and Efficacy of Natural Health Products.

2007 ◽  
Vol 85 (11) ◽  
pp. 1099-1107 ◽  
Author(s):  
B. Chauhan ◽  
C. Yu ◽  
A. Krantis ◽  
I. Scott ◽  
J. T. Arnason ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Moderate Activity ◽  
Natural Health Products ◽  
Natural Health ◽  
Herbal Products ◽  
Safety And Efficacy ◽  
Methanol Extracts ◽  
Metabolism Enzymes ◽  
Health Products

Some natural health products (NHPs) affect drug metabolism enzymes and transport proteins, potentially affecting the safety and efficacy of the drug or other NHPs. This study was undertaken to characterize the effect of uva-ursi ( Arctostaphylos uva-ursi ) on cytochrome P450 isozyme (3A4, 3A5, 3A7, 2C19, and 19)-mediated metabolism and P-glycoprotein (P-gp) transport. Three bulk and 2 capsulated uva-ursi samples were obtained from commercial outlets. The capsules were batched, and herbal samples were ground to a common consistency. Aqueous and methanol extracts were freshly prepared. Cytochrome P450 isozyme-mediated metabolism was determined by using in vitro bioassays. P-gp transport function was determined by using a rhodamine 123 (Rh123) uptake test in human (THP-1) monocytes and human Caco-2 cells. All products were analyzed by HPLC for arbutin, gallic acid, myricitrin, and isoquercetin. A large variation was observed in the biomarkers found between the bulk and capsulated samples. Our data indicate that both the aqueous and methanol extracts of all 5 uva-ursi products showed high cytochrome P450 isozyme inhibition, with the exception of the methanol extracts against cytochromes P3A4 and P19, which had low to moderate activity. The aqueous extracts of uva-ursi showed an inhibitory effect on Rh123 efflux by P-gp at 1 h and an inductive effect at 18 h for both cell lines. Our results show that the uva-ursi herbal products tested here have pharmacological properties, including the potential capacity to affect drug safety and efficacy. Further studies are warranted against a wider range of cytochrome P450 isozymes and to determine whether these effects are clinically significant.

scholarly journals Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

2021 ◽  
Author(s):  
Lawrence Howell ◽  
Rosalind E. Jenkins ◽  
Stephen Lynch ◽  
Carrie Duckworth ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Rna Polymerase Ii ◽  
Liver Tissue ◽  
Drug Disposition ◽  
Multiple Drug ◽  
Proteomic Profiling ◽  
Cytochrome P450 3A ◽  
Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

NATURAL HEALTH PRODUCTS AND DRUG DISPOSITION

2005 ◽  
Vol 45 (1) ◽  
pp. 203-226 ◽  
Author(s):  
Brian C. Foster ◽  
J. Thor Arnason ◽  
Colin J. Briggs
Keyword(s):  
Health Care Professionals ◽  
Adverse Drug Events ◽  
Drug Disposition ◽  
Natural Health Products ◽  
Confounding Factors ◽  
Natural Health ◽  
Herbal Products ◽  
Health Products ◽  
History Of ◽  
Human Use

Botanicals such as herbal products (HPs) and nutraceuticals (NCs) are often regarded as low risk because of their long history of human use. Anecdotal and literature reports of adverse drug events (ADEs) and clinical studies with HPs are increasing, but many of the reports are incomplete and contradictory. These reports need to identify confounding factors and explain contradictory findings if they are to help health care professionals or patients understand what risks are involved. HPs are complex botanicals, not single-active ingredient (SAI) products. Studies can be confounded by different manufacturing processes and formulations, including cosmetics and food supplements; environment; chemotypes; misidentification or adulteration; and factors associated with the patient or user population such as use, total drug load, and genetics. Future studies need to be conducted with characterized product that includes all commercially available related products. Clinical trials should be relevant to the user population and take into account the confounding factors that may influence the interpretation of the findings.

scholarly journals Melatonin Interaction Resulting in Severe Sedation

2015 ◽  
Vol 18 (2) ◽  
pp. 124 ◽  
Author(s):  
Brian C Foster ◽  
Kosta Cvijovic ◽  
Heather S Boon ◽  
Teresa W Tam ◽  
Rui Liu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Surveillance ◽  
Cytochrome P450 Enzyme ◽  
Natural Health Products ◽  
Pharmacodynamic Interaction ◽  
Health Products ◽  
Vitro Analysis ◽  
Pharmacologically Active ◽  
In Vitro Analysis

Purpose. Natural health products (NHPs), including melatonin, are widely used products. Despite the widespread assumption that all NHPs are safe, they contain pharmacologically active substances and can therefore have adverse effects and/or interact with pharmaceuticals. Objective: To investigate the mechanism underlying NHP interactions identified through the Pharmacy SONAR active surveillance study. Methods: Active surveillance was undertaken in community pharmacies to identify adverse events in patients who had recently taken NHPs together with conventional pharmaceuticals. For suspected NHP-pharmaceutical interactions, the possible mechanism of action was explored by in vitro analysis of samples of different products to identify cytochrome P450 enzyme (CYP) inhibition potential. Results: Active surveillance identified a 19-year-old male taking citalopram, nortriptyline and oxycodone concomitantly and who experienced severe sedation when melatonin was added to this regimen. In vitro analysis involving several melatonin products showed product-dependent inhibition of CYP1A2, CYP2C19 and CYP3A7. Conclusion: The adverse event was likely due to a primary pharmacokinetic interaction between melatonin and citalopram; although mechanistically, interactions affecting cytochrome P450-mediated metabolism may have occurred with all of these health products. A pharmacodynamic interaction may also be possible, but beyond the capacity of this study to establish.Key words: Melatonin, citalopram, nortriptyline, oxycodone, drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Selection and Micropropagation of an Elite Melatonin Rich Tulsi (Ocimum sanctum L.) Germplasm Line

Agronomy ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Mukund R. Shukla ◽  
Annaliese Kibler ◽  
Christina E. Turi ◽  
Lauren A. E. Erland ◽  
J. Alan Sullivan ◽  
...  
Keyword(s):  
In Vitro Selection ◽  
Integrated Approach ◽  
Antioxidant Potential ◽  
Ocimum Sanctum ◽  
Natural Health Products ◽  
Seed Population ◽  
Health Products ◽  
Potential Applications ◽  
Medicinal Properties

Tulsi (Ocimum sanctum L.) is a sacred plant of medicinal and spiritual significance in many cultures. Medicinal properties of Tulsi are ascribed to its phytochemicals with antioxidant capabilities. The current study was undertaken to screen a large seed population of Tulsi to select germplasm lines with high antioxidant potential and to standardize protocols for micropropagation and biomass production to produce a phytochemically consistent crop. A total of 80 germplasm lines were established under in vitro conditions and screened for their antioxidant potential determined with the 2,2-diphenyl-1-picrylhydrazyl (DPPH) bioassay. The micropropagation of a selected line, named Vrinda, was established using nodal cultures grown on Murashige and Skoog medium containing benzylaminopurine (1.1 µM), gibberellic acid (0.3 µM), and activated charcoal (0.6%). The antioxidant phytohormones melatonin and serotonin were quantified in the field and greenhouse grown tissues of Vrinda and melatonin levels were found to be consistent in both conditions with higher serotonin levels under field conditions. This integrated approach combining the in vitro selection and propagation offers potential applications in the development of safe, effective, and novel natural health products of Tulsi, and many other medicinal plant species.

scholarly journals Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

2021 ◽  
Vol 8 ◽  
Author(s):  
Emre Karakus ◽  
Clarissa Prinzinger ◽  
Silke Leiting ◽  
Joachim Geyer
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Gene Deletion ◽  
Homologous Sequence ◽  
Pharmacokinetic Studies ◽  
Metabolizing Enzymes ◽  
Genomic Level ◽  
Very High

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. However, as the first available canine genome sequences all were CYP2C41 negative, this polymorphism could not be clarified at the genomic level. The present study provides an exact characterization of the CYP2C41 gene deletion polymorphism at the genomic level and presents a PCR-based genotyping method that was used for CYP2C41 genotyping of 1,089 individual subjects from 36 different dog breeds. None of the Bearded Collie, Bernese Mountain, Boxer, Briard, French Bulldog or Irish Wolfhound subjects had the CYP2C41 gene in their genomes. In contrast, in the Chinese Char-Pei, Siberian Husky, Schapendoes and Kangal breeds, the CYP2C41 allele frequency was very high, with values of 67, 57, 43, and 34%, respectively. Interestingly, the site of gene deletion was identical for all CYP2C41 negative dogs, and all CYP2C41 positive dogs showed highly homologous sequence domains upstream and downstream from the CYP2C41 gene. CYP2C41 genotyping can now be routinely used in future pharmacokinetic studies in canines, in order to identify genetically-based poor or extensive drug metabolizers. This, together with more extensive in vitro drug screening for CYP2C41 substrates will help to determine the clinical relevance of CYP2C41, and to optimize drug treatment. Although the relative abundance of the CYP2C41 protein in the canine liver seems to not be very high, this CYP could substantially contribute to hepatic drug metabolism in dogs expressing CYP2C41 from both alleles and, when CYP2C41 shows higher catalytic activity to a given drug than other hepatic metabolic enzymes.

scholarly journals Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives

2021 ◽  
Vol 22 (21) ◽  
pp. 11500
Author(s):  
Anshul Sharma ◽  
Hyo-Kyoung Choi ◽  
Yeon-Kye Kim ◽  
Hae-Jeung Lee
Keyword(s):  
Molecular Mechanisms ◽  
Future Research ◽  
Natural Health Products ◽  
Cell Protection ◽  
Anticancer Properties ◽  
Dietary Antioxidant ◽  
Health Products ◽  
Antioxidant Supplements

Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin.

Nitric Oxide Mediates Hepatic Cytochrome P450 Dysfunction Induced by Endotoxin

1996 ◽  
Vol 84 (6) ◽  
pp. 1435-1442 ◽  
Author(s):  
Claudia M. Muller ◽  
Annette Scierka ◽  
Richard L. Stiller ◽  
Yong-Myeong Kim ◽  
Ryan D. Cook ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Sprague Dawley ◽  
Cytochrome P450 Content ◽  
Nitrate Concentrations ◽  
Hypnotic Drugs ◽  
Plasma Nitrite

Background Animals subjected to immunostimulatory conditions (sepsis) exhibit decreased total cytochrome P450 content and decreased P450-dependent drug metabolism. Cytochrome P450 function is of clinical significance because it mediates the metabolism of some opioid and hypnotic drugs. The authors tested the hypothesis that reduced P450 function and decreased drug metabolism in sepsis are mediated by endotoxin-enhanced synthesis of nitric oxide. Methods Hepatic microsomes were prepared from male Sprague-Dawley rats in nontreated rats, rats pretreated with phenobarbital and rats receiving aminoguanidine or NG-L-monomethyl-arginine alone. Nitric oxide synthesis was augmented for 12 h with a single injection of bacterial lipopolysaccharides. Nitric oxide synthase was inhibited with aminoguanidine or N(G)-L-monomethyl-arginine during the 12 h of endotoxemia in some animals. Plasma nitrite and nitrate concentrations were measured in vivo, and total microsomal P450 content, and metabolism of ethylmorphine and midazolam in vitro. Results Administration of endotoxin increased plasma nitrite and nitrate concentrations, decreased total cytochrome P450 content, and decreased metabolism of ethylmorphine and midazolam. Inhibition of nitric oxide formation by aminoguanidine or N(G)-L-monomethyl-arginine partially prevented the endotoxin-induced effects in the nontreated and phenobarbital-treated groups. Aminoguanidine or N(G)-L-monomethyl-arginine alone did not have an effect on either total cytochrome P450 content or P450-dependent drug metabolism. Plasma nitrite and nitrate concentrations correlated significantly negatively with P450 content (nontreated r = -0.88, phenobarbital r = -0.91), concentrations of formed formaldehyde (nontreated r = -0.87, phenobarbital r = -0.95), and concentrations of midazolam metabolites (4-OH midazolam nontreated r = -0.88, phenobarbital r = -0.93, and 1'-OH midazolam nontreated r = -0.88, phenobarbital r = -0.97). Conclusions Altered hepatic microsomal ethylmorphine and midazolam metabolism during sepsis is mediated in large part by nitric oxide.

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