Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.

Nat Genet. 2019 08;51(8):1252-1262

Authors: Song M, Yang X, Ren X, Maliskova L, Li B, Jones IR, Wang C, Jacob F, Wu K, Traglia M, Tam TW, Jamieson K, Lu SY, Ming GL, Li Y, Yao J, Weiss LA, Dixon JR, Judge LM, Conklin BR, Song H, Gan L, Shen Y

Abstract
Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

PMID: 31367015 [PubMed - indexed for MEDLINE]

Combination of BRAF and MEK inhibition in BRAF V600E mutant low-grade ganglioglioma.

J Clin Pharm Ther. 2020 Jan 27;:

Authors: Yau WH, Ameratunga M

Abstract
WHAT IS KNOWN AND OBJECTIVE: Post-surgical management of low grade gangliogliomas is controversial with paucity of data for the use of chemotherapy. BRAF mutations are present in a number of glioma subtypes and offer an opportunity for treatment with targeted therapy.
CASE SUMMARY: A 32-year-old man with an unresectable, BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial radiological and clinical response was noted after 13 weeks of treatment. Treatment complication with grade 2 skin and liver toxicity was resolved with dose interruption and reduction.
WHAT IS NEW AND CONCLUSION: Combination BRAF and MEK inhibition present a safe and feasible treatment strategy in unresectable BRAF V600E mutant low grade ganglioglioma.

PMID: 31985841 [PubMed - as supplied by publisher]

Childhood asthma in the new omics era: challenges and perspectives.

Curr Opin Allergy Clin Immunol. 2020 Jan 24;:

Authors: Golebski K, Kabesch M, Melén E, Potočnik U, van Drunen CM, Reinarts S, Maitland-van der Zee AH, Vijverberg SJH, PERMEABLE consortium

Abstract
PURPOSE OF REVIEW: Childhood asthma is a heterogeneous inflammatory disease comprising different phenotypes and endotypes and, particularly in its severe forms, has a large impact on the quality-of-life of patients and caregivers. The application of advanced omics technologies provides useful insights into underlying asthma endotypes and may provide potential clinical biomarkers to guide treatment and move towards a precision medicine approach.
RECENT FINDINGS: The current article addresses how novel omics approaches have shaped our current understanding of childhood asthma and highlights recent findings from (pharmaco)genomics, epigenomics, transcriptomics, and metabolomics studies on childhood asthma and their potential clinical implications to guide treatment in severe asthmatics.
SUMMARY: Until now, omics studies have largely expanded our view on asthma heterogeneity, helped understand cellular processes underlying asthma, and brought us closer towards identifying (bio)markers that will allow the prediction of treatment responsiveness and disease progression. There is a clinical need for biomarkers that will guide treatment at the individual level, particularly in the field of biologicals. The integration of multiomics data together with clinical data could be the next promising step towards development individual risk prediction models to guide treatment. However, this requires large-scale collaboration in a multidisciplinary setting.

PMID: 31985545 [PubMed - as supplied by publisher]

Fractions of Boswellia serrata suppress LTA4, LTC4, Cyclooxygenase-2 activities and mRNA in HL-60 Cells and reduce lung inflammation in BALB/c mice.

Curr Drug Discov Technol. 2020 Jan 26;:

Authors: Soni KK, Meshram D, Lawal TO, Patel U, Mahady GB

Abstract
BACKGROUND: Purified fractions from a Boswellia serrata Roxb. Ex. Colebr. (Burseraceae) extract (ETOH and DCM) contain biologically active compounds that are well known for having inflammation inhibitory properties. In this work, the purified fractions were tested in-vitro for LTC4, LTA4 and COX-2 activities using ELISA and qPCR was performed to determine gene regulation in human leukemia (HL-60) Cells. Two D-imaging tomography was performed to determine the anti-inflammatory activities of the fractions in BALB/c mouse model of lung inflammation.
OBJECTIVE: To evaluate anti-inflammatory activities of bioactive compounds of Boswellia serrata purified fractions.
METHODS: In-vitro MTT assay was performed in HL-60 cell lines for measuring the toxicity/viability of the cells. ELISA tests were performed for evaluating LTA4, LTC4 and COX-2 activities. qPCR was performed to evaluate the expression of mRNA in HL-60 cells. In-vivo experiments were performed in OVA sensitized and challenged BALB/c mice at two doses of Boswellia serrata purified fraction containing 6% Boswellic acid of 50 and 100mg/kg body weight were given orally and the standard drug dexamethasone (DXA, 4 mg/kg body weight) and reduction in lung inflammation was assessed by using an IVIS Xenogen in-vivo fluorescence imaging system.
RESULTS: A purified fraction of Boswellia serrata ETOH extracts reduced leukotriene-C4-synthase activity by 52%, leuktotriene-A4-hydrolase activity by 22% and COX-2 activity by 99% with an IC50 of 12.5µg/ml. Intragastric administration of the purified fraction of Boswellia serrata at two doses of 50mg/kg b.w. and 100mg/kg b.w., respectively along with 2-3% HPMC resulted in a ~51% (P value <0.01) reduction in OVA induced lung inflammation in BALB/c mice as observed by imaging tomography. Treatment of the OVA challenged mice with a standard drug dexamethasone (DXA) reduced inflammation by ~66% with significant value (P<0.0001).
CONCLUSION: The present study describes that Boswellia serrata ethanolic extracts purified fraction (ETOH-BS) possess significant anti-inflammatory activities in HL-60 and in BALB/c and further supports for its use as Ayurvedic medicines traditionally in the treatment of lung disorders including allergy and asthma.

PMID: 31985381 [PubMed - as supplied by publisher]

Insights into gastrointestinal microbiota-generated ginsenoside metabolites and their bioactivities.

Drug Metab Rev. 2020 Jan 26;:1-14

Authors: Yang L, Zou H, Gao Y, Luo J, Xie X, Meng W, Zhou H, Tan Z

Abstract
The gastrointestinal microbiota and host co-evolve into a complex 'super-organism,' and this relationship plays a vital role in many physiological processes, such as drug metabolism. Ginseng is an important medicinal resource and the main ingredients are ginsenosides, which are less polar, difficult to absorb, and have low bioavailability. However, studies have shown that the biological activity of ginsenosides such as compound K (CK), ginsenoside Rg3 (Rg3), ginsenoside Rh2 (Rh2), 20(S)-protopanaxatriol (20(S)-PPT), and 20(S)-protopanaxadiol (20(S)-PPD) is closely related to the gastrointestinal microbiota. In this paper, the metabolic pathway of gastrointestinal microbiota-generated ginsenosides and the main pharmacological effects of these metabolites are discussed. Furthermore, our study provides a new insight into the discovery of novel drugs. Specifically, in new drug screening process, candidates with low biological activity and bioavailability should not be excluded. Because their metabolites may exhibit good pharmacological effects due to the involvement of the gastrointestinal microbiota. In addition, in further research studies to develop probiotics, a combination of agents could exert greater efficacy than single agents. Moreover, differences in lifestyle and diet lead to differences in the gastrointestinal microbiota in the human body. Therefore, administration of the same drug dose to different individuals could elicit different therapeutic effects, owing to the involvement of the gastrointestinal microbiota. Thus, treatment accuracy could be achieved by detecting the gastrointestinal microbiota before drug treatment.HighlightsGastrointestinal microbiota plays a decisive role in bioactivities of ginsenosides.The metabolic pathway and main pharmacological effects of ginsenoside metabolites are discussed.It provides new insights into novel drug discovery and further research to find probiotic, combinations to exert greater efficacy.Differences in lifestyle and diet, varies the gastrointestinal microbiota in the human body. However, the same dose of a drug producing different therapeutic effects may involve gastrointestinal microbiota.

PMID: 31984805 [PubMed - as supplied by publisher]

Knowledge and attitudes on pharmacogenetics among pediatricians.

J Hum Genet. 2020 Jan 27;:

Authors: Rahawi S, Naik H, Blake KV, Owusu Obeng A, Wasserman RM, Seki Y, Funanage VL, Oishi K, Scott SA

Abstract
Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, <10% felt they were familiar with pharmacogenetics, which was very consistent with <20% of the U.S. pediatricians correctly responding to a codeine/CYP2D6 pharmacogenetics knowledge question and <10% of U.S. pediatricians being aware of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Despite being generally unfamiliar with pharmacogenetics, >80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.

PMID: 31983733 [PubMed - as supplied by publisher]

Association of HLA-A*11:01 with sulfonamide-related severe cutaneous adverse reactions in Japanese patients.

J Invest Dermatol. 2020 Jan 22;:

Authors: Nakamura R, Ozeki T, Hirayama N, Sekine A, Yamashita T, Yoichi Mashimo, Mizukawa Y, Shiohara T, Watanabe H, Sueki H, Ogawa K, Asada H, Kaniwa N, Tsukagoshi E, Matsunaga K, Niihara H, Yamaguchi Y, Aihara M, Mushiroda T, Saito Y, Morita E

PMID: 31981579 [PubMed - as supplied by publisher]

Impact of SLCO1B1 genetic variation on rosuvastatin systemic exposure in pediatric hypercholesterolemia.

Clin Transl Sci. 2020 Jan 25;:

Authors: Wagner JB, Abdel-Rahman S, Gaedigk A, Gaedigk R, Raghuveer G, Staggs VS, Van Haandel L, Steven Leeder J

Abstract
This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n=13; 521CC, n=2) and wild type controls (521TT, n=13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure amongst our pediatric cohort was comparable to previous studies in adults. Rosuvastatin concentration-time curve from 0 to 24h (AUC0-24 ) was 1.4- and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Inter-individual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~1.5- to 2-fold difference in mean RVA exposure observed between SLCO1B1 genotype groups, suggesting that other factors also contribute to inter-individual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~30% of the variability RVA AUC0-24 . However, of the statin investigated to date in the pediatric population, rosuvastatin has the lowest magnitude of variability in systemic exposure.

PMID: 31981411 [PubMed - as supplied by publisher]

Alternative Splicing in the Nuclear Receptor Superfamily Redirects Human Metabolic Homeostasis.

Drug Metab Dispos. 2020 Jan 24;:

Authors: Annalora AJ, Marcus CB, Iversen PL

Abstract
TThe human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endo-xenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable diversification of the 48 human NR genes, which are potentially processed into over 1000 distinct mRNA transcripts by alternative splicing (AS). The average human NR expresses ~21 transcripts per gene and is associated with ~7000 single nucleotide polymorphisms (SNP). However, the rate of SNP accumulation does not appear to drive the AS process, highlighting the resilience of NR genes to mutation. Here we summarize the altered tissue distribution/function of well-characterized NR splice variants associated with human disease. We also describe a cassette exon visualization pictograph (CEViP) methodology for illustrating the location of modular, cassette exons in genes, which can be skipped in-frame, to facilitate the study of their functional relevance to both drug metabolism and NR evolution. We find cassette exons associated with all of the functional domains of NR genes including the DNA- and ligand-binding domains. The matrix of inclusion or exclusion for functional domain-encoding cassette exons is extensive and capable of significant alterations in cellular phenotypes that modulate endo-xenobiotic metabolism. Exon inclusion options are differentially distributed across NR subfamilies, suggesting group-specific conservation of resilient functionalities. A deeper understanding of this transcriptional plasticity expands our understanding of how chemical signals are refined and mediated by NR genes. This expanded view of the NR transcriptome informs new models of chemical toxicity, disease diagnostics and precision-based approaches to personalized medicine. SIGNIFICANCE STATEMENT: This review explores the impact of AS on the human NR superfamily and highlights the dramatic expansion of >1,000 potential transcript variants from 48 individual genes. Xenobiotics are increasingly recognized for their ability to perturb gene splicing events, but the physiological impact of AS remains poorly understood. Here we explore the differential sensitivity of NR genes to AS and discuss how their differential expression profiles may augment cellular resilience to stress and fine-tune adaptive, metabolic responses to endo-xenobiotic exposure.

PMID: 31980501 [PubMed - as supplied by publisher]

Nanomedicine and Immunotherapy: A Step Further towards Precision Medicine for Glioblastoma.

Molecules. 2020 Jan 23;25(3):

Authors: Šamec N, Zottel A, Videtič Paska A, Jovčevska I

Abstract
Owing to the advancement of technology combined with our deeper knowledge of human nature and diseases, we are able to move towards precision medicine, where patients are treated at the individual level in concordance with their genetic profiles. Lately, the integration of nanoparticles in biotechnology and their applications in medicine has allowed us to diagnose and treat disease better and more precisely. As a model disease, we used a grade IV malignant brain tumor (glioblastoma). Significant improvements in diagnosis were achieved with the application of fluorescent nanoparticles for intraoperative magnetic resonance imaging (MRI), allowing for improved tumor cell visibility and increasing the extent of the surgical resection, leading to better patient response. Fluorescent probes can be engineered to be activated through different molecular pathways, which will open the path to individualized glioblastoma diagnosis, monitoring, and treatment. Nanoparticles are also extensively studied as nanovehicles for targeted delivery and more controlled medication release, and some nanomedicines are already in early phases of clinical trials. Moreover, sampling biological fluids will give new insights into glioblastoma pathogenesis due to the presence of extracellular vesicles, circulating tumor cells, and circulating tumor DNA. As current glioblastoma therapy does not provide good quality of life for patients, other approaches such as immunotherapy are explored. To conclude, we reason that development of personalized therapies based on a patient's genetic signature combined with pharmacogenomics and immunogenomic information will significantly change the outcome of glioblastoma patients.

PMID: 31979318 [PubMed - in process]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/01/25

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change.

NPJ Genom Med. 2020;5:1

Authors: Oni-Orisan A, Haldar T, Ranatunga DK, Medina MW, Schaefer C, Krauss RM, Iribarren C, Risch N, Hoffmann TJ

Abstract
In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

PMID: 31969989 [PubMed]

Human leukocyte antigen DRB1*04:05 and clozapine-induced agranulocytosis/granulocytopenia.

Aust N Z J Psychiatry. 2020 Jan 22;:4867419900296

Authors: Saito T, Ikeda M, Mushiroda T, Iwata N, Clozapine Pharmacogenomics Consortium of Japan (CPC-J)

PMID: 31968985 [PubMed - as supplied by publisher]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/01/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Genetics of Treatment Outcomes in Major Depressive Disorder: Present and Future.

Clin Psychopharmacol Neurosci. 2020 Feb 29;18(1):1-9

Authors: Fabbri C, Serretti A

Abstract
Pharmacogenetic testing is a useful and increasingly widespread tool to assist in antidepressant prescription. More than ten antidepressants (including tricyclics, selective serotonin reuptake inhibitors and venlafaxine) have already genetic biomarkers of response/side effects in clinical guidelines and drug labels. These are represented by functional genetic variants in genes coding for cytochrome enzymes (CYP2D6 and CYP2C19). Depending on the predicted metabolic activity, guidelines provide recommendations on drug choice and dosing. Despite not conclusive, the current evidence suggests that testing can be useful in patients who did not respond or tolerate at least one previous pharmacotherapy. However, the current recommendations are based on pharmacokinetic genes only (CYP450 enzymes), while pharmacodynamic genes (modulating antidepressant mechanisms of action in the brain) are still being studied because of their greater complexity. This may be captured by polygenic risk scores, which reflect the cumulative contribution of many genetic variants to a trait, and they may provide future clinical applications of pharmacogenetics. A more extensive use of genotyping in clinical practice may lead to improvement in treatment outcomes thanks to personalized treatments, but possible ethical issues and disparities should be taken into account and prevented.

PMID: 31958900 [PubMed]

Systematic Review and Meta-Analysis of the Moderating Effect of rs1799971 in OPRM1, the Mu-opioid Receptor Gene, on Response to Naltrexone Treatment of Alcohol Use Disorder.

Addiction. 2020 Jan 21;:

Authors: Hartwell EE, Feinn R, Morris PE, Gelernter J, Krystal J, Arias AJ, Hoffman M, Petrakis I, Gueorguieva R, Schacht JP, Oslin D, Anton RF, Kranzler HR

Abstract
BACKGROUND AND AIMS: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment.
METHODS: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percent heavy drinking days, percent days abstinent, and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model.
RESULTS: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, p = 0.02). However, the effect was not significant when multiple comparisons were taken into account.
CONCLUSIONS: From the evidence to date, it remains unclear whether Rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

PMID: 31961981 [PubMed - as supplied by publisher]

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings.

Clin Transl Sci. 2020 Jan 21;:

Authors: Smith DM, Peshkin BN, Springfield TB, Brown RP, Hwang E, Kmiecik S, Shapiro R, Eldadah Z, Lundergan C, McAlduff J, Levin B, Swain SM

Abstract
Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and non-academic settings. This was a retrospective analysis of 667 patients from a pilot in four perioperative and five outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and U.S. Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared to 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

PMID: 31961467 [PubMed - as supplied by publisher]

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Pharmacogenomics J. 2020 Jan 21;:

Authors: Borrego-Soto G, Perez-Paramo YX, Chen G, Santuario-Facio SK, Santos-Guzman J, Posadas-Valay R, Alvarado-Monroy FM, Balderas-Renteria I, Medina-Gonzalez R, Ortiz-Lopez R, Lazarus P, Rojas-Martinez A

Abstract
Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3'-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

PMID: 31959879 [PubMed - as supplied by publisher]

Pharmacometabonomics: The Prediction of Drug Effects Using Metabolic Profiling.

Handb Exp Pharmacol. 2019;260:263-299

Authors: Everett JR

Abstract
Metabonomics, also known as metabolomics, is concerned with the study of metabolite profiles in humans, animals, plants and other systems in order to assess their health or other status and their responses to experimental interventions. Metabonomics is thus widely used in disease diagnosis and in understanding responses to therapies such as drug administration. Pharmacometabonomics, also known as pharmacometabolomics, is a related methodology but with a prognostic as opposed to diagnostic thrust. Pharmacometabonomics aims to predict drug effects including efficacy, safety, metabolism and pharmacokinetics, prior to drug administration, via an analysis of pre-dose metabolite profiles. This article will review the development of pharmacometabonomics as a new field of science that has much promise in helping to deliver more effective personalised medicine, a major goal of twenty-first century healthcare.

PMID: 31823071 [PubMed - indexed for MEDLINE]

Co-delivery of 2-Deoxyglucose and a Glutamine Metabolism Inhibitor V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer.

Acta Biomater. 2020 Jan 17;:

Authors: Luo Z, Xu J, Sun J, Huang H, Zhang Z, Ma W, Wan Z, Liu Y, Pardeshi A, Li S

Abstract
The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells' compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier poly-(oligo ethylene glycol)-co-poly(4-((4-oxo-4-((4-vinylbenzyl)oxy)butyl)disulfaneyl)butanoic acid)-(2-deoxyglucose) (POEG-p-2DG) was developed. POEG-p-2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (∼10nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.

PMID: 31958597 [PubMed - as supplied by publisher]