Identification and characterization of amiodarone metabolites in rats using UPLC-ESI-QTOFMS-based untargeted metabolomics approach.

J Toxicol Environ Health A. 2018 Apr 11;:1-12

Authors: Jeong ES, Kim G, Yim D, Moon KS, Lee SJ, Shin JG, Kim DH

Abstract
Amiodarone is a class III anti-arrhythmic benzofuran derivative extensively utilized in treatment of life-threatening ventricular and supraventricular arrhythmias. However, amiodarone also produces adverse side effects including liver injury due to its metabolites rather than parent drug. The purpose of the present study was to identify metabolites of amiodarone in the plasma and urine of rats administered the drug by using an untargeted metabolomics approach. Drug metabolites were profiled by ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and results subjected to multivariate data analysis. A total of 49 amiodarone metabolites were identified and their structures were characterized by tandem mass spectrometry. Amiodarone metabolites are presumed to be generated via five major types of metabolic reactions including N-desethylation, hydroxylation, carboxylation (oxo/hydroxylation), de-iodination, and glucuronidation. Data demonstrated that an untargeted metabolomics approach appeared to be a reliable tool for identifying unknown metabolites in a complex biological matrix.

PMID: 29641932 [PubMed - as supplied by publisher]

Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay.

Genet Test Mol Biomarkers. 2018 Mar 19;:

Authors: Langaee T, Wagner R, Horne LP, Lawson LA, Becker C, Shahin M, Starostik P, Stacpoole PW

Abstract
AIMS: Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1). Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans. We aimed to develop a sensitive and rapid clinical genetic screening test for determining GSTZ1 haplotype status in individuals who would be treated with DCA, and then apply the test for the investigation of the plasma pharmacokinetics (PK) of DCA as a function of GSTZ1 haplotype.
MATERIALS AND METHODS: DNA samples from 45 healthy volunteer study participants were genotyped for three functional GSTZ1 single nucleotide polymorphisms (rs7975, rs7972, and rs1046428) by TaqMan®. Prior studies showed that subjects with at least one EGT haplotype (EGT carrier) metabolized DCA faster than EGT noncarriers. The clinical genetic test for GSTZ1 was developed and validated at our CLIA-certified Clinical Laboratory. Four fast metabolizer EGT carriers and four slow metabolizer EGT noncarriers were selected to complete a standard PK study. Each participant received a single oral dose of 25 mg/kg of DCA (IND 028625) for 5 days.
RESULTS: The EGT haplotype carrier group demonstrated significantly faster metabolism of DCA and higher rates of plasma DCA clearance after 5 days of drug exposure compared with EGT noncarriers (p = 0.04).
CONCLUSIONS: These preliminary data establish the validity and practicality of our rapid genotyping/haplotyping procedure for genetic-based DCA dosing to mitigate or prevent adverse effects in patients treated chronically with this drug.

PMID: 29641284 [PubMed - as supplied by publisher]

Corrigendum.

Pharmacogenomics. 2018 Apr 11;:

Authors:

PMID: 29637802 [PubMed - as supplied by publisher]

12 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 2018/04/11

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.

A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years.

Pharmacogenomics. 2018 Apr 09;:

Authors: Moghadam AR, Mehramiz M, Entezari M, Aboutalebi H, Kohansal F, Dadjoo P, Fiuji H, Nasiri M, Aledavood SA, Anvari K, Simab SA, Khorrami MS, Moradi A, Hassanian SM, Ferns GA, Sales SS, Avan A

Abstract
AIM: Esophageal cancer is the eighth most common cancer globally and the seventh most common cause of cancer-related deaths in men. Recent studies have shown that CYP450, family 1, subfamily B, polypeptide 1, which plays a role in the metabolism of xenobiotics, is associated with several cancers. Therefore, in the present study we investigated the association between a genetic variant, CYP1B1-rs1056836 gene, with the clinical characteristics of patients with squamous cell carcinoma of the esophagus (ESCC).
METHOD: In this study, 117 patients with ESCC and 208 healthy controls were recruited. DNA was extracted and genotyped using real-time PCR-based TaqMan. Kaplan-Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between clinicopathological data, genotypic frequencies, disease prognosis and survival, Pearson's χ2 and t-test were used. Logistic regression was utilized to assess the association between the risk of ESCC and genotypes.
RESULTS:  The genotypic frequency for GG, GC and CC were 58.6, 29.8 and 11.5%, respectively, in the healthy subjects and 51.8, 36.14 and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Also, statistically significant results were not found for this variation and risk of ESCC.
CONCLUSION: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger populations in different ethnic groups, taking into account potentially important environmental factors such as diet.

PMID: 29629838 [PubMed - as supplied by publisher]

CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration.

Pharmacogenomics. 2018 Apr 09;:

Authors: Pasternak AL, Zhang L, Hertz DL

Abstract
Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration.

PMID: 29629825 [PubMed - as supplied by publisher]

Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a meta-analysis.

Pharmacogenomics. 2018 Apr 09;:

Authors: Liu Y, Yu Y, Nie X, Zhao L, Wang X

Abstract
AIM: HLA-B*15:02 has been demonstrated as a key risk factor for carbamazepine-induced severe cutaneous adverse reaction (sCAR), especially in Asian population. Oxcarbazepine (OXC) is a drug that has a similar structure of carbamazepine. However, the relationship between HLA-B*15:02 and induced cutaneous adverse reaction (cADR) remains unknown. This study aims to analyze this association in the published literature.
METHOD: After filtering studies, eight studies were finally included for meta-analysis, including 32 sCAR cases, 112 mild cutaneous adverse reaction (mcADR) cases, 281 OXC tolerant control and 946 population control cases.
RESULT: In the tolerant control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR (odds ratio [OR]: 18.13; 95% CI: 6.77-48.56), but not in mcADR (OR: 1.43; 95% CI: 0.56-3.64). In population control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR, (OR: 8.22; 95% CI: 3.03-22.34), but not in mcADR (OR: 2.06; 95% CI: 0.91-4.67).
DISCUSSION: Our study demonstrates that the genetic risk factor HLA-B*15:02 may be a factor in OXC-induced sCAR.

PMID: 29629814 [PubMed - as supplied by publisher]

The 9p21 locus as a potential therapeutic target and prognostic marker in colorectal cancer.

Pharmacogenomics. 2018 Apr 09;:

Authors: Bahrami A, Hassanian SM, Khazaei M, Gharib M, Rahmani M, Fiuji H, Jazayeri MH, Moetamani-Ahmadi M, Ferns GA, Avan A

Abstract
Colorectal cancer (CRC) is a major cause of cancer-related-death worldwide. Despite extensive efforts to identify valid biomarkers for the risk stratification of CRC patients, there are few of proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to CRC. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CRC. Several genetic polymorphisms have been identified in this region that are associated with CRC. Three genes are located at this locus; CDKN2B(encoding-p15ink4b), CDKN2A (encoding-p16ink4a/p14ARF) and 3' end of CDKN2BAS (termed-antisense-noncoding-RNA in the INK4-locus [ANRIL]). ANRIL has a post-transcriptional modulatory activity, which has been shown to perturb the expression of nearby genes. It also plays an important role in coordinating tissue remodeling through regulation of cell proliferation, apoptosis, aging, extra-cellular matrix remodeling and inflammatory response. However, the role of ANRIL is not well understood in CRC. Hypermethylation of the p14ARF and p16INK4a genes is often found in some tumors, including CRC. However, further studies are necessary to explore the clinical utility of these putative markers in risk stratification, and in the assessment of prognosis. In this review, we have summarized the prognostic and therapeutic potential of the p14ARF and p16INK4a genes in patients with colorectal cancer.

PMID: 29629612 [PubMed - as supplied by publisher]

Identification of novel CYP4F2 genetic variants exhibiting decreased catalytic activity in the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE).

Prostaglandins Leukot Essent Fatty Acids. 2018 Apr;131:6-13

Authors: Kim WY, Lee SJ, Min J, Oh KS, Kim DH, Kim HS, Shin JG

Abstract
CYP4F2 is an enzyme involved in the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid and metabolizes vitamin K into an inactive form. Our objectives were to identify new CYP4F2 genetic variants and to characterize the functional consequences of the conversion of arachidonic acid into 20-HETE. We used direct DNA sequencing to identify a total of 20 single-nucleotide polymorphisms (SNPs) including four coding variants, A27V, R47C, P85A, and V433M, in 50 randomly selected subjects. Of these, A27V and P85A were new. Recombinant variant proteins were prepared using an Escherichia coli expression system, purified, and quantified via CO-difference spectral analysis. The conversion of arachidonic acid to 20-HETE by the coding variants was compared to that of the wild-type protein. Wild-type CYP4F2 exhibited the highest intrinsic clearance, followed by P85A, A27V, V433M, and R47C (40-65% of the wild-type value). The locations of the mutated residues in the three-dimensional protein structure were predicted by structural modeling, and the possible effects on 20-HETE synthesis discussed. In summary, we describe the allele frequency, haplotype distribution, and linkage disequilibrium of CYP4F2 and functionally analyze the CYP4F2 coding variants. Our findings suggest that individuals having the low-activity alleles of CYP4F2 may inefficiently convert arachidonic acid into 20-HETE. This may aid in our understanding of 20-HETE-related blood pressure problems and cardiovascular diseases when genotype-phenotype association studies are performed in the future.

PMID: 29628049 [PubMed - in process]

Novel Applications of Metabolomics in Personalized Medicine: A Mini-Review.

Molecules. 2017 Jul 13;22(7):

Authors: Li B, He X, Jia W, Li H

Abstract
Interindividual variability in drug responses and disease susceptibility is common in the clinic. Currently, personalized medicine is highly valued, the idea being to prescribe the right medicine to the right patient. Metabolomics has been increasingly applied in evaluating the therapeutic outcomes of clinical drugs by correlating the baseline metabolic profiles of patients with their responses, i.e., pharmacometabonomics, as well as prediction of disease susceptibility among population in advance, i.e., patient stratification. The accelerated advance in metabolomics technology pinpoints the huge potential of its application in personalized medicine. In current review, we discussed the novel applications of metabolomics with typical examples in evaluating drug therapy and patient stratification, and underlined the potential of metabolomics in personalized medicine in the future.

PMID: 28703775 [PubMed - indexed for MEDLINE]

Genetically determined enlargement of carotid body evaluated using computed angiotomography.

Respir Physiol Neurobiol. 2018 Apr 05;:

Authors: Jaźwiec P, Gać P, Chaszczewska-Markowska M, Bogunia-Kubik K, Mazur G, Poręba R

Abstract
It has recently been established that carotid bodies play a significant role in the regulation of activities of the cardiovascular system as well as in the pathogenesis of arterial hypertension, heart failure and diabetes. Aim of study was to determinate the influence of polymorphisms within genes of the renin-angiotensin-aldosterone system (RAAS) on the volume of the carotid bodies (CB) in patients with hypertension (HTA). The study group consisted of 77 patients with HTA. All patients were genotyped for single-nucleotide polymorphisms of genes coding for: angiotensinogen: rs4762, rs5049, rs5051 and rs699; angiotensin-converting enzyme: rs4343; angiotensin receptor type 1 gene (AGTR1): rs5182 and rs5186; and the aldosterone synthase: rs1799998. The estimation of volumes of CB (VrCB+lCB) was based on computed tomography angiography. Among individuals with essential hypertension certain relationships were documented between rs5182 and rs5186 polymorphisms of AGTR1 gene and rs1799998 polymorphism of CYP11B2 gene on one hand and the volume of carotid bodies on one other. Patients carrying the C alleles within the rs5182 and rs5186 of AGTR1 gene was associated with higher values of VrCB+lCB. The carriage of the T allele in the rs5182 locus of the AGTR1 gene determine lower values of VrCB+lCB. In summary, in patients with HTA a higher volume of CB may be resulted from the presence of specific genotypes in RAAS.

PMID: 29627490 [PubMed - as supplied by publisher]

12/15 lipoxygenase: A crucial enzyme in diverse types of cell death.

Neurochem Int. 2018 Apr 05;:

Authors: Li QQ, Qin-Li, Jia JN, Liu ZQ, Zhou HH, Mao XY

Abstract
The 12/15-lipoxygenase (12/15-LOX) enzymes react with polyunsaturated fatty acids producing active lipid metabolites that are involved in plethora of human diseases including neurological disorders. A great many of elegant studies over the last decades have contributed to unraveling the mechanism how 12/15-lipoxygenase play a role in these diseases. And the way it works is mainly through apoptosis. However, recent years have found that the way 12/15-lipoxygenase works is also related to autophagy and ferroptosis, a newly defined type of cell death by Stockwell's lab in 2012. Figuring out how 12/15-lipoxygenase participate in these modes of cell death is of vital importance to understand its role in disease. The review aims to give a sight on our current knowledge on the role of this enzyme in apoptosis, autophagy and ferroptosis. And the relevant diseases that 12/15-lipoxygenase may be involved.

PMID: 29627380 [PubMed - as supplied by publisher]

The combined effects of cardiovascular disease related SNPs on ischemic stroke.

J Neurol Sci. 2018 May 15;388:141-145

Authors: Xu K, Liu X, Ott J, Jiang F, Zhang W, Wang L, Zhao J, Wang X

Abstract
PURPOSE: Previous studies have revealed multiple common variants associated with known risk factors for cardiovascular disease (CVD). Ischemic stroke (IS) and CVD share several risk factors with each having substantial heritability. We aimed to generate a multi-locus genetic risk score (GRS) for IS based on CVD related SNPs to evaluate their combined effects on IS.
METHODS: A total of 851 patients and 977 controls were selected from Beijing, Tianjin, Shandong, Shanxi, Shaanxi and Heilongjiang communities. The candidate genes were genotyped by PCR-hybridization. Information about demographic factors, history of disease (such as hypertension), and lifestyle was obtained using structured questionnaires. A GRS model weighted by the absolute value of regression coefficient β was established to comprehensively assess the association between candidate SNPs and IS. Using the area under the receiver operating characteristic curve (AUC) to evaluate the value of GRS on predicting IS.
RESULTS: The GRS of cases was 2.87 ± 0.28, which was significantly higher than controls' GRS (2.78 ± 0.30) (P < 0.000). With the increase of the GRS, the risk of IS became higher (Ptrend < 0.000). Subjects in the top quartile of the GRS had about 1.9-fold increased risk of IS compared with subjects in the lowest quartile (OR adjusted = 1.880, 95%CI = 1.442-2.452, P < 0.000). The AUC = 0.580, P < 0.000.
CONCLUSION: 13 CVD related SNPs had combined effects on IS. The GRS of cases was significantly higher than controls' GRS. As the GRS increased, the risk of IS increased. The GRS model has some value for the prediction of IS.

PMID: 29627009 [PubMed - in process]

Determination of plasma Levetiracetam level by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) and its application in pharmacokinetics studies in neonates.

J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Mar 27;1085:13-20

Authors: Jenjirattithigarn N, Worachat N, Horsuwan S, Puangpetch A, Prempunpong C, Khongkhatithum C, Thampratankul L, Prommas S, Visudtibhan A, Sukasem C

Abstract
BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug which has good safety and efficacy in neonatal seizure (NS), a common incident in neonates with weight <1500 g. The pharmacokinetics for LEV in neonatal populations is yet to be clearly understood. In this study, we developed and validated a method for determination of LEV in plasma by liquid chromatography tandem mass spectrometry for the purpose of pharmacokinetic study.
METHODS: Plasma LEV was spiked with Lamivudine as internal standard before extraction by C18 solid-phase extraction (SPE) cartridge. Chromatography was performed using isocratic elution with mobile phase A: B (10: 90) for 2.0 min with flow rate 0.4 mL/min. The mobile phase was composed of 0.1% formic acid in 10.0 mM ammonium acetate (A) and 100% methanol (B). The injection volume was 1.0 μL and the total run time was 2.0 min. Multiple reaction monitoring (MRM) with electro spray in positive mode was used. The mass transition for LEV was 171.2/126.0 and 230.0/112.0 for IS with retention time of 0.73 and 0.72 min, respectively.
RESULTS: A calibration curve range from 0.50-80.0 μg/mL was obtained with a correlation coefficient >0.99 in the quadratic model. Precision and accuracy was within the acceptable range and the intra- and inter-day %CV for three concentrations of QCs were <10%.
CONCLUSION: This method was reliable, accurate and applicable for LEV pharmacokinetic study in neonates with seizure.

PMID: 29626789 [PubMed - as supplied by publisher]

Sulfotransferase 4A1 (SULT4A1) increases its expression in mouse neurons as they mature.

Drug Metab Dispos. 2018 Apr 06;:

Authors: Hashiguchi T, Shindo S, Chen SH, Hong JS, Negishi M

Abstract
Cytosolic sulfotransferases (SULTs) catalyze sulfation and play essential roles in detoxification of xenobiotics as well as inactivation of endo-biotics. Sulfotransferase 4A1 (SULT4A1) which was originally isolated as a brain-specific sulfotransferase, is the most highly conserved isoform among SULTs in vertebrates. Here, expression of SULT4A1 was examined neuron enriched and neuron-glia mixed cells derived from mouse embryo brains at day 14 gestation and mixed glia from 2 days-old neonate brains. Western blots showed an increase of SULT4A1 expression as neurons maturated. RT-PCR and agarose gel analysis found two different forms (variant and wild type) of SULT4A1 mRNA in neurons; the level of wild type correlates with the protein level of SULT4A1. SULT1E1 was expressed neither in mouse brains, neuron enriched cells nor mixed glia cells. SULT1A1 protein was only detected in adult brains. Immunofluorescence staining of neuron-glia mixed cells confirmed selective expression of SULT4A1 in neurons including dopaminergic neurons, but not in either astrocytes or microglia. Thus, SULT4A1 is a neuron-specific sulfotransferase and may play a role in neuronal development.

PMID: 29626075 [PubMed - as supplied by publisher]

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 2018/04/07

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.

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 2018/04/07

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.

Proton Pump Inhibitors: from CYP2C19 Pharmacogenetics to Precision Medicine.

Expert Opin Drug Metab Toxicol. 2018 Apr 05;:

Authors: El Rouby N, Lima JJ, Johnson JA

Abstract
Introduction- Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered-This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion-There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

PMID: 29620484 [PubMed - as supplied by publisher]

Clinical pharmacogenetics: how do we ensure a favorable future for patients?

Pharmacogenomics. 2018 Apr 05;:

Authors: Wiltshire T, Dong OM

Abstract
Currently, there is sufficient evidence for the use of pharmacogenetic information to optimize medication prescribing, but why has this information not been integrated into the drug prescribing process to improve patient care? A discussion about the major contributing factors that have limited the use of pharmacogenetic information in the drug prescribing process, the solutions to ensure widespread uptake, and a vision for the future of the pharmacogenetic field will be explored.

PMID: 29620450 [PubMed - as supplied by publisher]

Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease.

Pharmacogenomics. 2018 Apr 05;:

Authors: Jhun EH, Hu X, Sadhu N, Yao Y, He Y, Wilkie DJ, Molokie RE, Wang ZJ

Abstract
AIM: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients.
METHODS: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain.
RESULTS & CONCLUSION: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

PMID: 29620434 [PubMed - as supplied by publisher]