Samuel Martín‐Vílchez

Universidad Autónoma de Madrid

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Ricardo Moreno‐Otero

Hospital Universitario de La Princesa

P. Sanz-Cameno

Instituto de Salud Carlos III

Manuel Román

Hospital Universitario de La Princesa

Francisco Abad‐Santos

Universidad Autónoma de Madrid

Y. Rodríguez-Muñoz

Hospital Universitario de La Princesa

M.J. Borque

Universidad de Jaén

Gina Mejía‐Abril

Hospital Universitario de La Princesa

Luisa García‐Buey

Universidad Autónoma de Madrid

Manuel López‐Cabrera

Centro de Biología Molecular Severo Ochoa

Dolores Ochoa

Universidad Autónoma de Madrid

Cooperative Institutions

Hospital Universitario de La Princesa

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Centro de Investigación Biomédica en Red

Consejo Superior de Investigaciones Científicas

Universidad Complutense de Madrid

Universidad de Alcalá

Research Institute Hospital 12 de Octubre

Spanish Clinical Research Network

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Papers

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Histone modifications associated with biological drug response in moderate‐to‐severe psoriasis

Experimental Dermatology (2018)

María C. Ovejero‐Benito Alejandra Reolid Patricia Sánchez‐Jiménez Miriam Saiz‐Rodríguez Ester Muñoz‐Aceituno

Abstract Introduction Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate‐to‐severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. Objective To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). Materials and methods Peripheral blood mononuclear cells ( PBMC s) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMC s. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA . Data were analysed by IBM ‐ SPSS v.23. Results and conclusions Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non‐significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non‐responders to biological drugs at 3 months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non‐responders to biological drugs at 3 and 6 months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients’ response to biological drugs in psoriasis.

Ixekizumab

Ustekinumab

10.1111/exd.13790

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Citations (62)

α-Actinin-2 Mediates Spine Morphology and Assembly of the Post-Synaptic Density in Hippocampal Neurons

PLoS ONE (2014)

Jennifer Hodges Samuel Martín‐Vílchez Hannelore Asmussen Leanna Whitmore Alan Rick Horwitz

Dendritic spines are micron-sized protrusions that constitute the primary post-synaptic sites of excitatory neurotransmission in the brain. Spines mature from a filopodia-like protrusion into a mushroom-shaped morphology with a post-synaptic density (PSD) at its tip. Modulation of the actin cytoskeleton drives these morphological changes as well as the spine dynamics that underlie learning and memory. Several PSD molecules respond to glutamate receptor activation and relay signals to the underlying actin cytoskeleton to regulate the structural changes in spine and PSD morphology. α-Actinin-2 is an actin filament cross-linker, which localizes to dendritic spines, enriched within the post-synaptic density, and implicated in actin organization. We show that loss of α-actinin-2 in rat hippocampal neurons creates an increased density of immature, filopodia-like protrusions that fail to mature into a mushroom-shaped spine during development. α-Actinin-2 knockdown also prevents the recruitment and stabilization of the PSD in the spine, resulting in failure of synapse formation, and an inability to structurally respond to chemical stimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor. The Ca2+-insensitive EF-hand motif in α-actinin-2 is necessary for the molecule's function in regulating spine morphology and PSD assembly, since exchanging it for the similar but Ca2+-sensitive domain from α-actinin-4, another α-actinin isoform, inhibits its function. Furthermore, when the Ca2+-insensitive domain from α-actinin-2 is inserted into α-actinin-4 and expressed in neurons, it creates mature spines. These observations support a model whereby α-actinin-2, partially through its Ca2+-insensitive EF-hand motif, nucleates PSD formation via F-actin organization and modulates spine maturation to mediate synaptogenesis.

Filopodia

Dendritic filopodia

Actinin

10.1371/journal.pone.0101770

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Citations (41)

Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety

Pharmaceutics (2023)

Paula Soria‐Chacartegui Pablo Zubiaur Dolores Ochoa Gonzalo Villapalos‐García Manuel Román

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t1/2) (univariate p-value (puv) = 0.039, multivariate p-value (pmv) = 0.013, β = -5.31, R2 = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC72/DW) (puv = 0.025; pmv = 0.026, β = 578.90, R2 = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6, SLC22A1 and CYP3A4. In addition to the previous associations, CYP2D6 UMs showed a lower AUC72/DW (puv = 0.046, pmv = 0.049, β = -68.80, R2 = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain (puv = 0.038) and dizziness (puv = 0.038, pmv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1. Further research is needed to gather more evidence before its application in clinical practice.

Amlodipine

Variation (astronomy)

10.3390/pharmaceutics15020404

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Citations (9)

The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection

Reviews in Medical Virology (2011)

Samuel Martín‐Vílchez Enrique Lara‐Pezzi María Trapero-Marugán Ricardo Moreno‐Otero P. Sanz-Cameno

SUMMARY Hepatitis B virus is considered one of the most significant environmental carcinogens in humans. Because the mechanisms of HBV replication and the development of hepatocellular carcinoma (HCC) are partially known, HBV‐associated pathogenesis remains a challenge to increase its understanding. Evidence suggests that the regulatory protein hepatitis B virus X (HBx) mediates the establishment and maintenance of the chronic carrier state. HBx is a multifunctional and potentially oncogenic protein that is conserved among mammalian hepadnaviruses; it is produced very early after infection and throughout the chronic phase. HBx exerts its effects by interacting with cellular proteins and activating various signaling pathways. HBx stimulates the transcription of genes that regulate cell growth, apoptosis, and DNA repair. It also interacts with proteasome subunits and affects mitochondrial stability. Moreover, HBx participates in processes that are associated with the progression of chronic liver disease, including angiogenesis and fibrosis. This review discusses the function of HBx in the life cycle of HBV and its contribution to the pathogenesis of HCC. Copyright © 2011 John Wiley & Sons, Ltd.

HBx

Pathogenesis

Hepatitis B

Viral life cycle

10.1002/rmv.699

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Citations (47)

306 Imbalance of intrahepatic angiogenic factors expression in primary biliary cirrhosis patients

Journal of Hepatology (2004)

P. Sanz-Cameno Samuel Martín‐Vílchez Janaína Braga Medina Luisa Garcı́a-Buey Manuel López‐Cabrera

Primary Biliary Cirrhosis

Primary (astronomy)

Intrahepatic Cholangiocarcinoma

10.1016/s0168-8278(04)90306-6

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Citations (0)

Polymorphisms in histone deacetylases improve the predictive value of IL-28B for chronic hepatitis C therapy

Genes and Immunity (2013)

Rosario López‐Rodríguez Ángel Hernández‐Bartolomé M.J. Borque Y. Rodríguez-Muñoz Samuel Martín‐Vílchez

HDAC3

Histone deacetylase 2

Pegylated interferon

10.1038/gene.2013.24

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Citations (10)

Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients

Revista Española de Enfermedades Digestivas (2005)

X. Salcedo Mora P. Sanz-Cameno J. Medina Samuel Martín‐Vílchez Luisa Garcı́a-Buey

Objectives: our objectives were to compare angiogenesis soluble factor (ASF) levels in chronic hepatitis C (CHC) patients and healthy individuals, and to investigate potential associations between ASF levels and both histological and biochemical markers of disease progression.Method: thirty-six patients (69% males) positive for HCV-RNA by PCR analysis were included in the study.All patients underwent liver biopsy before treatment.Serum levels of vascular endothelial growth factor (VEGF), soluble Flt-1 and Flk-1 receptors, placental growth factor (PlGF), angiopoietin-2 (Ang-2) and soluble Tie-2 receptor were determined by ELISA.Fifteen healthy subjects were used as controls.Results: in comparison to healthy individuals, CHC patients showed significantly increased serum levels of proangiogenic factors PlGF (22 ± 5 vs. 18 ± 8 pg/ml; p < 0.05), Ang-2 (1265 ± 385 vs. 833 ± 346 pg/ml; p < 0.005) and sFlt-1 (95 ± 22 vs. 72 ± 14 pg/ml; p < 0.0001).Interestingly, in CHC patients serum levels of VEGF and Tie-2 correlated with grade of inflammation, PlGF correlated with stage of fibrosis, and Flt-1 and Flk-1 correlated with serum transaminase levels (p < 0.05 in all cases).Conclusions: CHC patients showed increased serum levels of ASF, and a significant correlation was shown between serum levels of selected ASFs and grade of inflammation, stage of fibrosis, and transaminase levels.

Liver disease

Aspartate transaminase

10.4321/s1130-01082005001000003

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Citations (25)

SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Journal of Personalized Medicine (2021)

Pablo Zubiaur Maria Dolores Benedicto Gonzalo Villapalos‐García Marcos Navares‐Gómez Gina Mejía‐Abril

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

SLCO1B1

10.3390/jpm11030204

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Citations (25)

An Investigational Study on the Role of CYP2D6, CYP3A4 and UGTs Genetic Variation on Fesoterodine Pharmacokinetics in Young Healthy Volunteers

Pharmaceuticals (2024)

Andrea Rodríguez‐Lopez Dolores Ochoa Paula Soria‐Chacartegui Samuel Martín‐Vílchez Marcos Navares‐Gómez

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (Cmax/DW)), elimination (terminal half-life (T1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and Cmax/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and Cmax/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, Cmax, and CL/F of 5-HMT, which should be confirmed in other studies.

Bioequivalence

Active metabolite

SLCO1B1

10.3390/ph17091236

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Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

Basic & Clinical Pharmacology & Toxicology (2018)

Carmen Belmonte Dolores Ochoa Manuel Román Miriam Saiz‐Rodríguez Aneta Wojnicz

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC0-t , Cmax and t1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC0-t (p = 0.039) and Cmax of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0-t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.

Aripiprazole

Bioequivalence

10.1111/bcpt.12960

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Citations (68)