Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 91

Publication Record

Connections

Gut Microbiome and Response to Cardiovascular Drugs.
Tuteja S, Ferguson JF
(2019) Circ Genom Precis Med 12: 421-429
MeSH Terms: Animals, Bacteria, Biotransformation, Cardiovascular Agents, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans
Show Abstract · Added March 3, 2020
The gut microbiome is emerging as an important contributor to both cardiovascular disease risk and metabolism of xenobiotics. Alterations in the intestinal microbiota are associated with atherosclerosis, dyslipidemia, hypertension, and heart failure. The microbiota have the ability to metabolize medications, which can results in altered drug pharmacokinetics and pharmacodynamics or formation of toxic metabolites which can interfere with drug response. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications. In this review, we will highlight mechanisms by which the gut microbiome facilitates the biotransformation of drugs and impacts pharmacological efficacy. A better understanding of the complex interactions of the gut microbiome, host factors, and response to medications will be important for the development of novel precision therapeutics for targeting CVD.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to Implementation.
Roden DM, Van Driest SL, Wells QS, Mosley JD, Denny JC, Peterson JF
(2018) Circ Res 122: 1176-1190
MeSH Terms: Biological Variation, Individual, Biotransformation, Cardiovascular Agents, Drug Development, Drug-Related Side Effects and Adverse Reactions, Forecasting, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genomics, Genotyping Techniques, Human Genome Project, Humans, Pharmacogenetics, Precision Medicine, Randomized Controlled Trials as Topic, Risk Assessment, Sample Size
Show Abstract · Added March 24, 2020
This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges.
© 2018 American Heart Association, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Mechanism of isoniazid-induced hepatotoxicity: then and now.
Metushi I, Uetrecht J, Phillips E
(2016) Br J Clin Pharmacol 81: 1030-6
MeSH Terms: Antitubercular Agents, Biotransformation, Chemical and Drug Induced Liver Injury, Humans, Isoniazid
Show Abstract · Added March 30, 2020
Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. Previous mechanistic hypotheses have classified this type of drug-induced liver injury (DILI) as 'metabolic idiosyncrasy' which was thought not to involve an immune response and was mainly due to the bioactivation of the acetylhydrazine metabolite. However, more recent studies support an alternative hypothesis, specifically, that INH itself is directly bioactivated to a reactive metabolite, which in some patients leads to an immune response and liver injury. Furthermore, there appear to be two phenotypes of INH-induced liver injury. Most cases involve mild liver injury, which resolves with immune tolerance, while other cases appear to have a more severe phenotype that is associated with the production of anti-drug/anti-CYP P450 antibodies and can progress to liver failure.
© 2016 The British Pharmacological Society.
0 Communities
1 Members
0 Resources
MeSH Terms
Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.
Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E
(2015) J Control Release 220: 751-7
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Biological Availability, Biotransformation, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Chemistry, Pharmaceutical, Cross-Linking Reagents, Cytochrome P-450 CYP3A, Delayed-Action Preparations, Dose-Response Relationship, Drug, Drug Carriers, Drug Stability, Female, Gastric Juice, Glucuronosyltransferase, Intestinal Secretions, Kinetics, Mice, Nanomedicine, Nanoparticles, Particle Size, Polyesters, Quercetin, Solubility, Tamoxifen
Show Abstract · Added February 15, 2016
We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.
Copyright © 2015 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
27 MeSH Terms
Aromatic hydroxylation of salicylic acid and aspirin by human cytochromes P450.
Bojić M, Sedgeman CA, Nagy LD, Guengerich FP
(2015) Eur J Pharm Sci 73: 49-56
MeSH Terms: Aspirin, Benzaldehydes, Biotransformation, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Deferoxamine, Enzyme Inhibitors, Humans, Hydroxylation, Isoenzymes, Microsomes, Liver, NADP, Organophosphates, Oxidation-Reduction, Reactive Oxygen Species, Recombinant Proteins, Salicylic Acid
Show Abstract · Added March 14, 2018
Aspirin (acetylsalicylic acid) is a well-known and widely-used analgesic. It is rapidly deacetylated to salicylic acid, which forms two hippuric acids-salicyluric acid and gentisuric acid-and two glucuronides. The oxidation of aspirin and salicylic acid has been reported with human liver microsomes, but data on individual cytochromes P450 involved in oxidation is lacking. In this study we monitored oxidation of these compounds by human liver microsomes and cytochrome P450 (P450) using UPLC with fluorescence detection. Microsomal oxidation of salicylic acid was much faster than aspirin. The two oxidation products were 2,5-dihydroxybenzoic acid (gentisic acid, documented by its UV and mass spectrum) and 2,3-dihydroxybenzoic acid. Formation of neither product was inhibited by desferrioxamine, suggesting a lack of contribution of oxygen radicals under these conditions. Although more liphophilic, aspirin was oxidized less efficiently, primarily to the 2,5-dihydroxy product. Recombinant human P450s 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the 5-hydroxylation of salicylic acid. Inhibitor studies with human liver microsomes indicated that all six of the previously mentioned P450s could contribute to both the 5- and 3-hydroxylation of salicylic acid and that P450s 2A6 and 2B6 have contributions to 5-hydroxylation. Inhibitor studies indicated that the major human P450 involved in both 3- and 5-hydroxylation of salicylic acid is P450 2E1.
Copyright © 2015 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals.
Rendic S, Guengerich FP
(2015) Chem Res Toxicol 28: 38-42
MeSH Terms: Biotransformation, Humans, Oxidoreductases, Xenobiotics
Show Abstract · Added January 20, 2015
Analyzing the literature resources used in our previous reports, we calculated the fractions of the oxidoreductase enzymes FMO (microsomal flavin-containing monooxygenase), AKR (aldo-keto reductase), MAO (monoamine oxidase), and cytochrome P450 participating in metabolic reactions. The calculations show that the fractions of P450s involved in the metabolism of all chemicals (general chemicals, natural, and physiological compounds, and drugs) are rather consistent in the findings that >90% of enzymatic reactions are catalyzed by P450s. Regarding drug metabolism, three-fourths of the human P450 reactions can be accounted for by a set of five P450s: 1A2, 2C9, 2C19, 2D6, and 3A4, and the largest fraction of the P450 reactions is catalyzed by P450 3A enzymes. P450 3A4 participation in metabolic reactions of drugs varied from 13% for general chemicals to 27% for drugs.
0 Communities
1 Members
0 Resources
4 MeSH Terms
Impact of structural and metabolic variations on the toxicity and carcinogenicity of hydroxy- and alkoxy-substituted allyl- and propenylbenzenes.
Rietjens IM, Cohen SM, Fukushima S, Gooderham NJ, Hecht S, Marnett LJ, Smith RL, Adams TB, Bastaki M, Harman CG, Taylor SV
(2014) Chem Res Toxicol 27: 1092-103
MeSH Terms: Animals, Benzene Derivatives, Biotransformation, Carcinogens, Humans
Show Abstract · Added June 1, 2014
The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood and can often provide a rationale for the comparison of toxicity based on structural analogy, at times quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this perspective, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy-substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical-based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only but should include an analogy of metabolic pathways across compounds and species.
0 Communities
1 Members
0 Resources
5 MeSH Terms
Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.
Murayama N, van Beuningen R, Suemizu H, Guillouzo CG, Shibata N, Yajima K, Utoh M, Shimizu M, Chesné C, Nakamura M, Guengerich FP, Houtman R, Yamazaki H
(2014) Chem Res Toxicol 27: 304-308
MeSH Terms: Aryl Hydrocarbon Hydroxylases, Biotransformation, Cell Line, Cells, Cultured, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP3A, Hepatocytes, Humans, Pregnane X Receptor, Protein Array Analysis, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Thalidomide
Show Abstract · Added March 10, 2014
Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. ( ( 2013 ) Chem. Res. Toxicol. 26 , 486 - 489 ) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pretreatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting the activation of upstream transcription factors involved in detoxication, e.g., the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of coregulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 coregulator-derived nuclear receptor-interaction motifs and coregulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5-hydroxythalidomide displayed significant modulation of coregulator interaction with PXR and CAR ligand-binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Influence of dietary fat type on benzo(a)pyrene [B(a)P] biotransformation in a B(a)P-induced mouse model of colon cancer.
Diggs DL, Myers JN, Banks LD, Niaz MS, Hood DB, Roberts LJ, Ramesh A
(2013) J Nutr Biochem 24: 2051-63
MeSH Terms: Animals, Aryl Hydrocarbon Hydroxylases, Benzo(a)pyrene, Biotransformation, Carcinogens, Chromatography, Thin Layer, Colon, Colonic Neoplasms, Cytochrome P-450 CYP1B1, DNA Adducts, Dietary Fats, Disease Models, Animal, Liver, Male, Mice
Show Abstract · Added March 7, 2014
In the US alone, around 60,000 lives/year are lost due to colon cancer. Diet and environment have been implicated in the development of sporadic colon tumors. The objective of this study was to determine how dietary fat potentiates the development of colon tumors through altered B(a)P biotransformation, using the Adenomatous polyposis coli with Multiple intestinal neoplasia mouse model. Benzo(a)pyrene was administered to mice through tricaprylin, and unsaturated (USF; peanut oil) and saturated (SF; coconut oil) fats at doses of 50 and 100 μg/kg via oral gavage over a 60-day period. Blood, colon, and liver were collected at the end of exposure period. The expression of B(a)P biotransformation enzymes [cytochrome P450 (CYP)1A1, CYP1B1 and glutathione-S-transferase] in liver and colon were assayed at the level of protein, mRNA and activities. Plasma and tissue samples were analyzed by reverse phase high-performance liquid chromatography for B(a)P metabolites. Additionally, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the (32)P-postlabeling method using a thin-layer chromatography system. Benzo(a)pyrene exposure through dietary fat altered its metabolic fate in a dose-dependent manner, with 100 μg/kg dose group registering an elevated expression of B(a)P biotransformation enzymes, and greater concentration of B(a)P metabolites, compared to the 50 μg/kg dose group (P<.05). This effect was more pronounced for SF group compared to USF group (P<.05). These findings establish that SF causes sustained induction of B(a)P biotransformation enzymes and extensive metabolism of this toxicant. As a consequence, B(a)P metabolites were generated to a greater extent in colon and liver, whose concentrations also registered a dose-dependent increase. These metabolites were found to bind with DNA and form B(a)P-DNA adducts, which may have contributed to colon tumors in a subchronic exposure regimen.
© 2013.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.
Wen W, Wu W, Romaine IM, Kaufmann K, Du Y, Sulikowski GA, Weaver CD, Lindsley CW
(2013) Bioorg Med Chem Lett 23: 4562-6
MeSH Terms: Biotransformation, Drug Discovery, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Models, Molecular, Molecular Structure, Pharmaceutical Preparations, Protein Binding, Structure-Activity Relationship
Show Abstract · Added February 16, 2015
This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.
Copyright © 2013 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
8 MeSH Terms