Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde.

Information is scarce regarding pharmacokinetic-based herb-drug interactions (HDI) with -cinnamaldehyde (CA) and 2-methoxycinnamaldehyde (MCA), components of cinnamon. Given the presence of cinnamon in food and herbal treatments for various diseases, HDIs involving the CYP2A6 substrates nicotine and letrozole with MCA (K = 1.58 µM; Hill slope = 1.

Critical functions of the polyamine putrescine for proliferation and viability of Leishmania donovani parasites.

Polyamines are metabolites that play important roles in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania parasites. However, little is known about the function of polyamines in parasites. To address this question, we assessed the effect of polyamine depletion in Leishmania donovani mutants lacking ornithine decarboxylase (Δodc) or spermidine synthase (Δspdsyn).

Forecasting academic success through implementation of an online prerequisite review tutorials program for first year pharmacy students.

Objective: Online prerequisite review (OPR) tutorials were designed and implemented to reinforce foundational scientific material in order to protect in-class time, foster self-directed learning, and ensure all students have similar baseline knowledge.

Methods: Twenty-one tutorials covering undergraduate prerequisite material were developed by faculty and organized into six core modules, comprising basic biology, chemistry, and physiology topics. A quiz on this material was given on the first day of each course.

Expanding the view of breast cancer metabolism: Promising molecular targets and therapeutic opportunities.

The changes in breast cancer cells that contribute to tumor evolution, heterogeneity, metastasis and ultimately drug resistance are shaped by numerous genetic changes including alterations in cellular metabolism. These include intermediary metabolic pathways such as glycolysis, the citric acid cycle oxidative phosphorylation, amino acid synthesis and lipid metabolism. However, cancer cells also exhibit key alterations in other metabolic pathways involved in drug metabolism such as cytochrome P450 enzymes, sulfotransferase and steroid sulfatases that are involved in the synthesis of estrogens and themselves serve as drug targets.

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole.

Human exposure to trans-cinnamic aldehyde [t-CA; cinnamaldehyde; cinnamal; (E)-3-phenylprop-2-enal] is common through diet and through the use of cinnamon powder for diabetes and to provide flavor and scent in commercial products. We evaluated the likelihood of t-CA to influence metabolism by inhibition of P450 enzymes. IC50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC50 = 6.

Allosteric modulation of substrate motion in cytochrome P450 3A4-mediated xylene oxidation.

Many cytochrome P450 enzymes (CYPs) exhibit allosteric behavior reflecting a complex ligand-binding process involving numerous factors: conformational selection, protein-protein interactions, substrate/effector/protein structure, and multiple-ligand binding. The interplay of CYP plasticity and rigidity contributes to substrate/product selectivity and to allosterism. Detailed evidence describing how protein motion modulates product selectivity is incomplete as are descriptions of effector-induced modulation of substrate dynamics.

Covalent modification and time-dependent inhibition of human CYP2E1 by the meta-isomer of acetaminophen.

The hypothesis that N-acetyl-m-aminophenol (AMAP), the meta isomer of acetaminophen, will covalently bind to and inhibit human CYP2E1 in a time- and NADPH-dependent manner was investigated. Liquid chromatography/electrospray ionization-mass spectrometry analysis indicated that AMAP metabolites (i.e.

Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: comparison of plasma and protein-free media incubation conditions.

Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC(50) that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor(s) with those obtained with protein-containing incubations. Seventeen CYP3A, CYP2C9, or CYP2D6 inhibitors were incubated with hepatocytes in human plasma or hepatocyte maintenance medium (HMM) for 20 min over a range of concentrations after which midazolam 1'-hydroxylation, diclofenac 4'-hydroxylation or (R)-bufuralol 1'-hydroxylation were used to quantify the corresponding cytochrome P450 (P450) catalytic activities.

Prediction of CYP3A-mediated drug-drug interactions using human hepatocytes suspended in human plasma.

Cryopreserved human hepatocytes suspended in human plasma (HHSHP) represent an integrated metabolic environment for predicting drug-drug interactions (DDIs). In this study, 13 CYP3A reversible and/or time-dependent inhibitors (TDIs) were incubated with HHSHP for 20 min over a range of concentrations after which midazolam 1'-hydroxylation was used to measure CYP3A activity. This single incubation time method yielded IC(50) values for the 13 inhibitors.

Multiple-ligand binding in CYP2A6: probing mechanisms of cytochrome P450 cooperativity by assessing substrate dynamics.

The contribution of ligand dynamics to CYP allosterism has not been considered in detail. On the basis of a previous study, we hypothesized that CYP2A6 and CYP2E1 accommodate multiple xylene ligands. As a result, the intramolecular ( k H/ k D) obs values observed for some xylene isomers are expected to be dependent on ligand concentration with contributions from [CYP.

A comparison of substrate dynamics in human CYP2E1 and CYP2A6.

Considering the dynamic nature of CYPs, methods that reveal information about substrate and enzyme dynamics are necessary to generate predictive models. To compare substrate dynamics in CYP2E1 and CYP2A6, intramolecular isotope effect experiments were conducted, using deuterium labeled substrates: o-xylene, m-xylene, p-xylene, 2,6-dimethylnaphthalene, and 4,4'-dimethylbiphenyl. Competitive intermolecular experiments were also conducted using d(0)- and d(6)-labeled p-xylene.