Absorption, Distribution, Metabolism, Elimination Research Articles

Identification of 1,2,4-Oxadiazoles-Based Novel EGFR Inhibitors: Molecular Dynamics Simulation-Guided Identification and in vitro ADME Studies.

BackgroundIn this work, we have identified heterocyclic derivatives with 1,2,4 oxadiazole scaffold mimicking the functions of tyrosine kinase inhibitors. Fourteen molecules that displayed the best fit were picked from the library of compounds and studied under in-silico and in-vitro conditions. Four compounds were selected for further cytotoxicity and ADME (Absorption, Distribution, Metabolism, Elimination) profiling showing IC50 (from 8–13 µM) values against EGFR positive cancer cell line (MCF7).MethodsA molecular dynamics simulation study was performed to understand the correlation of non-covalent binding energies with biological activity. The drug-like properties of the selected four compounds (7a, 7b, 7e, and 7m) were evaluated by in-vitro ADME studies. Compounds 7a, 7b, and 7m were the active compounds in the molecular dynamics simulations study. Further, EGFR binding activity was confirmed with EGFRWT and EGFRT790M kinase assay using a luminescence-based method.ResultsThese compounds (7a, 7b, and 7m) showed activity against EGFRWT and mutant EGFRT790M, exhibiting IC50 values of <10 and <50 micromolar, respectively. These compounds also possess moderate aqueous solubility in 40–70 µg/mL at pH 7.4 and 30–100 µg/mL at pH 4.0. Further, 7a, 7b, and 7m showed balanced lipophilicity with Log D values ranging from 1–3. They demonstrated a good correlation in Caco-2 permeability with Apparent permeability (Papp) 1 to 5 × 10−6 cm/s in comparison with 7e, which was found to be highly lipophilic (Log D >5) and showed high permeability (Papp 17 × 10−6 cm/s). Lastly, all these compounds were moderately stable in liver microsomes at alkaline pH with a half-life of 30–60 min, while at a highly acidic pH (2.0), the compounds were stable up to 15–20 min.ConclusionOverall, in-vitro ADME results of these molecules showed good drug-like properties, which are well correlated with the in-silico ADME data, making them ideal for developing an oral drug delivery formulation.

Synthesis of a dual carbon-14-labeled calcitonin gene-related peptide receptor antagonist for use in a human absorption-distribution-metabolism-elimination study.

Oral calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be effective in the acute and preventive treatment of migraine. CGRP receptor antagonists offer safety advantages over triptans because they are not active vasoconstrictors, which reduces cardiovascular risks. Bristol Myers Squibb discovered a high affinity CGRP receptor antagonist BMS-927711 for the treatment of migraine now FDA approved as Nurtec® ODT (rimegepant). Dual-labeled [14 C]-BMS-927711 was prepared and used in a human absorption-distribution-metabolism-elimination (ADME) study. A dual-labeled analog of BMS-927711 was required to fully track the compound's metabolic transformation. The carbon-14-labeled synthesis of both right side and left side portions of [14 C]-BMS-927711 is described.

QSAR, molecular docking, molecular dynamics and MM-GBSA approach for identification of prospective benzotriazole-based SARS-CoV 3CL protease inhibitors

The 3CL Protease of severe acute respiratory syndrome coronavirus (SARS-CoV), responsible for viral replication, has emerged as an essential target for designing anti-coronaviral inhibitors in drug discovery. In recent years, small molecule and peptidomimetic inhibitors have been used to target the inhibition of SARS-CoV 3CL Protease. In this study, we have developed 2D and 3D Quantitative structure activity relationship (QSAR) models on 3CL protease inhibitors with good predictive capability to propose inhibitors with improved affinities. Based on the 3 D contour maps, three new inhibitors were designed in silico, which were further subjected to molecular docking to explore their binding modes. The newly designed compounds showed improved interaction energies toward SARS-CoV-3CLPro due to additional interactions with the active site residues. The molecular docking studies of the most potent compounds revealed specific interactions with Glu 166 and Cys 145. Furthermore, absorption, distribution, metabolism, elimination (ADME) and drug-likeness evaluation revealed improved pharmacokinetic properties for these compounds. The molecular dynamics simulations confirmed the stability of the interactions identified by docking. The results presented would guide the development of new 3CL protease inhibitors with improved affinities in the future. Communicated by Ramaswamy H. Sarma

Synthesis, Molecular Docking, DFT and Antimicrobial Activity Studies of 2-(p-Fluorophenyl)-5-(2-(4- acetylpiperazin-1-yl)acetamido)benzoxazole

Bu çalışmada, yeni 2-(p-Florofenil)-5-(2-(4-asetilpiperazin-1-il)asetamido)benzoksazol bileşiği üç aşamada sentezlenmiş ve yapısı 1H-NMR ve 13C-NMR spektroskopisi ile aydınlatılmıştır. Antimikrobiyal aktivite çalışmaları, Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii NTCC 13304, Klebsiella pneumoniae ATCC 700603, Candida albicans ATCC 10231 ve bunların izolatları izolatları üzerinde gerçekleştirildi. Antimikrobiyal aktivite sonuçlarına göre, referans ilaçlar genel olarak daha iyi antimikrobiyal aktivite göstermesine rağmen sentezlenen bileşik, MİK: 32 µg mL-1 ile ampisilin ile karşılaştırıldığında E. faecalis izolatları ve E. coli izolatları üzerinde oldukça umut verici aktivite gösterdi. Moleküler doking çalışması DNA giraz subunit B yapısı üzerinde gerçekleştirildi. Teorik ADME (absorbsiyon, dağılım, metabolizma, eliminasyon) özellikleri hesaplandı. Ayrıca DFT/B3LYP yöntemi ve 6-311G (d,p) temel seti kullanılarak HOMO-LUMO enerjileri, moleküler elektrostatik potansiyel analizi ve optimize edilmiş geometrik yapısı belirlendi ve sonuçlar görüntülendi.

ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential.

On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. In this narrative review, we have evaluated the currently available ADME, PK, and DDI information about remdesivir and have discussed the potential of DDIs between remdesivir and different COVID-19 drug regimens and agents used for comorbidities. Considering the nascent status of remdesivir in the therapeutic domain, extensive future work is needed to formulate safer COVID-19 treatment guidelines involving this medication.

Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin-1,2,4-triazole scaffolds.

Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine-1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1 H and 13 C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure-activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.

Systemic pharmacological investigation of the Feng Shi Gu Tong capsule in the treatment of rheumatoid arthritis.

Feng Shi Gu Tong (FSGT) capsule is a commonly used Chinese Traditional Patent Medicine in clinical practice, which has been proven to be effective for the treatment of active rheumatoid arthritis (RA). However, due to its complex composition, the precise molecular mechanism of the FSGT capsule in the treatment of RA is still indistinct. Therefore, the method of systemic pharmacology was used to obtain candidate compounds through absorption, distribution, metabolism, elimination (ADME) parameters, and supplementation of references. Network construction and analysis were also included to reveal the potential mechanism of FSGT capsule in treating RA. A total of 119 compounds were obtained in FSGT capsule, and a total of 107 compounds with targets were included in the study. These compounds acted on 267 targets in total. In addition, there were 317 targets related to RA disease. All constructed networks included four major networks and four minor networks. In addition, the clusters of RA disease protein-protein interaction (PPI) network and FSGT capsule-RA disease targets network revealed that the biological process involved in these clusters including immune response and apoptosis, etc. The pathways enriched by the direct targets of FSGT capsule acted on RA also highly overlapped with the pathways enriched by the RA PPI network, such as the TNF signaling pathway. Our research has managed to predict and explain the pharmacological effects and the molecular mechanisms of the FSGT capsule in RA, and provided a realistic exploration method for studying the potentially active ingredients of traditional Chinese medicines simultaneously.

Design and in silico Evaluation of Some Pyridine Derivatives for Antihypertensive Activity

A novel series of 2,4,6-trisubstituted 1,4-dihydropyridine derivatives was designed and utilized for the computational studies for predicting absorption, distribution metabolism, elimination (ADME), pharmacological profile, toxicity and molecular docking of these derivatives. Some of the derivatives were found to have significant antihypertensive activity without toxicity.

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors.

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease.

Dementia is a neurological condition commonly correlated with Alzheimer’s disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (2a–2l) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (2a, 2b, 2d, 2e, 2g, 2i, and 2j) had a certain AChE inhibitory activity, and the IC50 values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound 2i was found to be the most active agent in the series with an IC50 value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds 2a, 2b, 2e, 2g, and 2i with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations.

Design, Synthesis, and Biological Activity Evaluation of New Donepezil-Like Compounds Bearing Thiazole Ring for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive and neurodegenerative disease that is primarily seen in the elderly population and is clinically characterized by memory and cognitive impairment. The importance of the disease has increased as a result of etiology of the disease having not yet been determined, an increase in patient population over the years, absence of radical treatment, high cost of treatment and care, and significant reduction in the quality of life of the patients, which have led researchers to direct more attention to this field. In a recent study, new indan-thiazolylhydrazone derivatives were designed and synthesized based on the chemical structure of the donepezil molecule, which is the most preferred and has the most appropriate response in the treatment of AD. The structures of the compounds were determined by 1H-NMR and 13C-NMR, and mass spectroscopic methods. Inhibition studies on the cholinesterase (ChE) enzymes and beta amyloid plaque inhibition test of the compounds were performed. Among the synthesized derivatives, compounds 2a, 2e, 2i, and 2l showed potent inhibitory activity on the AChE enzyme. Compound 2e was found to be the most active agent, with an IC50 value of 0.026 µM. The mechanism of AChE inhibition by compound 2e was studied using the Lineweaver-Burk plot, and the nature of inhibition was also determined to be mix-typed. Molecular docking studies were also carried out for compound 2e, which was found as the most potent agent within the AChE enzyme active site. Moreover, compounds 2a, 2e, 2i, and 2l displayed the ability to prevent beta amyloid plaque aggregation at varying rates. In addition, ADME (Absorption, Distribution, Metabolism, Elimination) parameters were evaluated for all synthesized compounds using the QikProp 4.8 software (Schrödinger Inc., NY, USA).

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics.

Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways—either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo—depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.

A novel strategy for prediction of human plasma protein binding using machine learning techniques

Plasma protein binding (PPB) is a key player of drug ADME (absorption, distribution, metabolism, elimination) behaviors, enabling PPB to have significant impact on drug efficacy and toxicity. As drug discovery enters the era of rational drug design, it is desirable to use in silico model to predict PPB so as to achieve rapid initial screening for potential candidate compounds prior to further time-consuming and costly in vitro and in vivo experimental assay. In this study, a global quantitative structure-activity relationship (QSAR) model of PPB was built on the basis of a large training set comprising more than 5000 compounds to represent large structural diversity. The uneven distribution of PPB was often rectified by two mathematical transformations of PPB but this led to a decrease in prediction accuracy at the lower binding level. To resolve this problem, we proposed a novel strategy to build models for different binding levels. The best model yielded much lower mean absolute error (MAE) of 0.076 on the test set than published models and the MAE was further reduced to 0.041 ​at the high level of binding (0.8–1). The models also performed excellent in the validation set containing some compounds from traditional Chinese medicine. In addition, the applicability domain was determined to identify new compounds which are appropriate for prediction using our built models. In conclusion, this study developed a novel strategy to construct robust QSAR model for PPB prediction which could be used by chemists to predict the PPB of candidate compounds efficiently and make structural modification in the early stage of drug development.

Synthesis of novel Azol-β-lactam derivatives starting from phenyl piperazine and investigation of their antiurease activity and antioxidant capacity comparing with their molecular docking studies

This study reports the synthesis, biological investigation and molecular docking of novel β-lactam derivatives bearing 1,3,4-thiadiazole and 1,3,4-oxadiazole ring system. The synthesized compounds were evaluated for in vitro antiurease activity and antioxidant capacity. Almost all compounds showed excellent antiurease activity compared to thiourea, standard drug. Also, in silico ADME (absorption, distribution, metabolism, elimination) prediction and molecular docking studies were performed.

Microphysiological system as a promising technology for drug assay

MPS (microphysiological system) is in-vitro cell-culture environment, which is precisely maintained in a micro space manufactured using MEMS (micro electro mechanical systems) technology, to derive in-vivo like functions from human cells. From the viewpoint of pharmacokinetics, it can be considered as a wet PBPK/PD simulator consisting of the micro organs (cell culture units) connected each other with a circulating medium, which mimic the organs responsible for the drug's ADME (absorption-distribution-metabolism-elimination). In this review, we identify two types of the cell culture units consisting of the MPS for pharmacokinetics, and overview the characteristics of each type. Then, we discuss about the technical requirements needed for the cell culture unit from the point of view of both cell-culture environmental design and cell function, and introduce the world-wide current situation of the commercialization of the MPS.

Elucidation of the Anti-Inflammatory Mechanisms of Bupleuri and Scutellariae Radix Using System Pharmacological Analyses.

Objective. This study was aimed at elucidating the molecular mechanisms underlying the anti-inflammatory effect of the combined application of Bupleuri Radix and Scutellariae Radix and explored the potential therapeutic efficacy of these two drugs on inflammation-related diseases. Methods. After searching the databases, we collected the active ingredients of Bupleuri Radix and Scutellariae Radix and calculated their oral bioavailability (OB) and drug-likeness (DL) based on the absorption-distribution-metabolism-elimination (ADME) model. In addition, we predicted the drug targets of the selected active components based on weighted ensemble similarity (WES) and used them to construct a drug-target network. Gene ontology (GO) analysis and KEGG mapper tools were performed on these predicted target genes. Results. We obtained 30 compounds from Bupleuri Radix and Scutellariae Radix of good quality as indicated by ADME assays, which possess potential pharmacological activity. These 30 ingredients have a total of 121 potential target genes, which are involved in 24 biological processes related to inflammation. Conclusions. Combined application of Bupleuri Radix and Scutellariae Radix was found not only to directly inhibit the synthesis and release of inflammatory cytokines, but also to have potential therapeutic effects against inflammation-induced pain. In addition, a combination therapy of these two drugs exhibited systemic treatment efficacy and provided a theoretical basis for the development of drugs against inflammatory diseases.

Molecular docking and high throughput screening of designed potent inhibitor to PTPN11 involved in Peptic Ulcer

In the current study we carried out computational drug designing and dock-ing studies on Tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Scaffold selection was based on the functional properties of PTPN11. Leads were identified based on several physiochemical properties and we created our library with those new molecules that were generated based on Lipinski's rule of five. Further, we carried out high throughput screening on 21 molecules from scaffolds selected. Screening of molecules was based on the criterions such as, TOPKAT (toxicity analysis) and ADMET (absorption, distribution, metabolism, elimination) properties. Among the ligands de-signed, only one compound was identified to have premium interaction within the targeted domain. Pharmacophore was generated and analyzed for selected drug candidate. Our results suggest that O-(3-hydroxy-4-methoxyphenyl) S-methyl dithio dicarbonate is a potent drug molecule in terms of physiochemical and docking properties. In conclusion, the identified compound has great potential to inhibit tyrosine-protein phosphatase non-receptor type 11 (PTPN11).

How to report and discuss ADME data in medicinal chemistry publications: in vitro data or in vivo extrapolations?

Early drug discovery projects often utilize data from ADME (absorption, distribution, metabolism, elimination) assays to benchmark data and guide discussion, rather than the predicted in vivo consequences of these data. Here, the two paradigms are compared, using evaluations of metabolic stability based on either microsomal clearance assay data or from the predicted in vivo hepatic clearance and half-life calculated through the combination of the venous well-stirred model and Øie-Tozer's model. The need for a shift in paradigm is presented, and its implications discussed. It is suggested that discussions about ADME data should revolve around potential clinical problems that are most likely to surface during the development phase, each benchmarked with a suitable variable derived from the assay data.

Recent Development of New Substituted Indole and Azaindole Derivatives as Anti-HIV Agents

Human immunodeficiency virus-1 (HIV-1) infections cause global health problems. Indole derivatives have been considered as one of the promising HIV inhibitors. Recent inventions have focused on substituted indole and azaindole derivatives that possess unique antiviral activities against HIV-1. In this review, the evaluation of recent advances in substituted indole and azaindole derivatives for the treatment or prevention of HIV-1 and acquired immune deficiency syndrome (AIDS) has been focused. In this respect, compounds having drug and bio-active properties, including their synthesis and pharmacologic properties have been reported. In addition, anti-HIV properties of compounds, the structural features of inhibitors, the current progress in terms of therapeutic interventions and the leading groups in the field are discussed. Moreover, clinical and ADME (Absorption, Distribution, Metabolism, Elimination) properties of some clinically important compounds such as BMS-378806, L-737126 and IDX899 are reported.

Genetic susceptibility to methylmercury developmental neurotoxicity matters

Epidemiological studies have demon-strated the developmental neurotoxicityassociated with prenatal methylmercuryexposure (Grandjean and Landrigan,2006); However, susceptibility tomethylmercury toxicity may be increasedby genetic factors. This observationraises the question of possible depen-dence of developmental neurotoxicity ongenetic predisposition. A few years ago, aNational Research Council (NRC) eval-uation of the scientific background forrisk assessment concluded that “atten-tion should be directed to vulnerableindividuals and subpopulations thatmay be particularly susceptible or morehighly exposed” (National ResearchCouncil, 2009). The panel also notedthat “variability in susceptibility andvulnerability has received less detailedevaluation in most EPA health effectsassessments.” A previous NRC reviewestimated that, under certain circum-stances, individual susceptibility couldrange up to 50,000-fold, and as muchas 5% of the population could well beat least 25-fold more susceptible thanthe average (National Research Council,2000).In risk assessment, an uncertaintyfactor of 10 is commonly used to takeinto account intraspecies susceptibil-ity. In regard to methylmercury, at therecommendation of the NRC (NationalResearch Council, 2009), EPA used thedefault 10-fold intraspecies uncertaintyfactor. In contrast, the European FoodSafety Authority recently argued that,for methylmercury, a partial uncer-tainty factor of 2 would be sufficientwhen a benchmark dose level (BMDL)hadbeenobtainedfromabirthcohortthat would represent the most vul-nerable population (European FoodSafety Authority, 2012). The magni-tude of the intraspecies uncertaintyfactor therefore appears controversial,and better scientific documentationhas been recommended (Dorne, 2010).Given that gene-environment interac-tion (GxE) may also play a role in regardto disease pathogenesis in a more gen-eral sense, as highlighted by a recentNIH workshop (Bookman et al., 2011),the variability in susceptibility to neu-rotoxicity between population groupsappears to be an important researchpriority.The recent findings on GxE formethylmercury neurotoxicity are sup-ported by several previous studies. Thus,mutations in certain genes seem to conveya greater risk of elemental mercury-associated neurobehavioral deficits orsymptoms in adults working in dentalclinics(Echeverriaetal.,2006,2010;Heyeret al., 2008, 2009). This evidence wasrecently extended to children exposed toinorganic mercury from amalgam fillings(Woodsetal.,2012,2013).Thereasonsforsuch interactions are only partially under-stood, but some gene variants may predictagreaterretentionofmercurycompoundsin the body.Thus, gene mutations seem to affectthe retention of inorganic mercury andmethylmercury in the body, e.g., genesthat affect glutathione (GSH) and metal-lothionein metabolism (Gundacker et al.,2007; Schlawicke Engstrom et al., 2008;Wang et al., 2012). Other studies havealso considered absorption-distribution-metabolism-elimination (ADME) genesthat may be of importance. Thus,methylmercury is eliminated from theliver as GSH conjugates, and the rate-limiting enzyme for GSH synthesis isglutamyl-cysteine ligase (GCL), which iscomposed of a catalytic subunit (GCLC)and a modifier subunit (GCLM). Further,the glutathione-S-transferases (GST) cat-alyze the conjugation of GSH (Gundackeret al., 2007). A recent study in Swedenindicates that a