Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance. (AU)

Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española / Association between single nucleotide genetic polymorphisms in ABC transporter genes with drug-resistant epilepsy in the Spanish population

Introducción: El 30% de los pacientes con epilepsia no responde al tratamiento farmacológico. La presencia de polimorfismos genéticos de nucleótido único (SNP) en el individuo puede influir en la variabilidad de respuesta al tratamiento farmacológico. La hipótesis de transportadores plantea que la presencia de SNP en los genes que codifican las proteínas ABC repercutiría en la biodisponibilidad de los fármacos anticrisis en el foco epileptógeno, lo que ocasionaría refractariedad. El objetivo del presente estudio fue evaluar la asociación de 13 polimorfismos en los genes ABCB1, ABCC2, ABCC5 y ABCG2 con la epilepsia farmacorresistente (EFR) en población española. Sujetos y métodos: Se realizó un estudio de casos y controles que incluyó a 327 pacientes con epilepsia: 227 farmacorresistentes y 100 farmacocontrolados según los criterios de la Liga Internacional contra la Epilepsia. En el ADN de leucocitos de sangre periférica extraído se estudiaron los polimorfismos en los genes transportadores ABC. Se utilizó la plataforma tecnológica iPlex® Gold y Mass ARRAY. Se compararon las frecuencias alélicas y genotípicas del grupo de casos y del de controles, el valor de p, la odds ratio y los intervalos de confianza al 95%. Resultados: La frecuencia alélica y genotípica del presente estudio fue similar a la comunicada en las bases de datos poblacionales. En los SNP estudiados no se encontraron diferencias significativas (p > 0,05) en todos los modelos de herencia analizados. Conclusiones: Nuestros resultados sugieren que no existe asociación entre los polimorfismos analizados en los genes ABC con la EFR en población española. Sin embargo, otros estudios adicionales confirmarán o descartarán estos resultados.(AU)

Introduction: Almost a third of all patients with epilepsy (30%) fail to respond to pharmacological treatment. The presence of single nucleotide polymorphisms (SNPs) in the individual may influence the variability of the response to drug treatment. The transporter hypothesis posits that the presence of SNPs in the genes encoding ABC proteins would affect the bioavailability of antiseizure drugs at the epileptogenic focus, giving rise to refractoriness. The aim of the present study was to evaluate the association of 13 polymorphisms in the ABCB1, ABCC2, ABCC5 and ABCG2 genes with drug-resistant epilepsy (DRE) in a Spanish population. Subjects and methods: A case-control study was conducted involving 327 patients with epilepsy: 227 resistant to drug therapy and 100 in whom their medication enabled them to control their symptoms, according to International League Against Epilepsy criteria. In the peripheral blood leukocyte DNA that was extracted, polymorphisms in the ABC transporter genes were studied. The iPlex® Gold and Mass ARRAY technology platform was used. The allele and genotypic frequencies of the case and control groups, p-value, odds ratio and 95% confidence intervals were compared. Results: The allele and genotypic frequency of the present study was similar to that reported in population-based databases. For the SNPs studied, no significant differences (p > 0.05) were found in any of the inheritance models analysed. Conclusions: Our results suggest that there is no association between the polymorphisms analysed in the ABC genes and DRE in the Spanish population. Nevertheless, further studies will confirm or refute these results.(AU)

Efectividad del tratamiento con sulfonilureas en paciente con mutación en el gen ABCC8 (MODY12) / Effectiveness of sulfonylurea treatment in a patient with a mutation in ABCC8 (MODY12)

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ABCA1 gene R1587K polymorphism could be associated with metabolic syndrome and increased plasma triglyceride concentration in adults from northern Mexico / El polimorfismo R1587K del gen ABCA1 podría estar asociado con el síndrome metabólico y la concentración elevada de triglicéridos en adultos del norte de México

INTRODUCTION: the ABCA1 protein plays a key role in reverse cholesterol transport, promoting its clearance and high-density lipoprotein (HDL) biogenesis. The R1587K (rs2230808) single-nucleotide polymorphism (SNP) in the ABCA1 gene has been associated with dyslipidemia. OBJECTIVES: to investigate the relationship of R1587K genotypes with cardiovascular (CV) risk, metabolic syndrome (MetS), lipid profile, paraoxonase-1 (PON1) activity, and anti-oxLDL titers. METHODS: we performed a cross-sectional study in 57 northern Mexican adults with no reported diseases. The ABCA1 R1587K SNP was detected by real-time polymerase chain reaction (qPCR) using TaqMan allelic discrimination probes. We evaluated the relationship of R1587K with metabolic syndrome and clinical parameters including lipid profile, glucose and insulin, PON1 activity and concentration, anti-oxLDL antibodies, anthropometry and body-composition parameters, and the atherogenic index of plasma calculation. RESULTS: our results show higher triglyceride levels in the RK + KK carriers as compared to RR carriers (p = 0.031). An association between the RK + KK genotype and the presence of MetS (OR = 4.566, 95% CI = 1.386-14.92, p = 0.010) and a tendency towards high CV risk (OR = 3.317, 95% CI = 0.910-8.611, p = 0.069) was observed in comparison to RR carriers; however, there were no differences in HDL-C levels, PON1 activity and concentration, and anti-oxLDL titers among the R1587K genotypes. CONCLUSIONS: in the northern Mexican population, the ABCA1 gene R1587K SNP is present and the RK + KK genotypes are associated with MetS and increased triglyceride concentrations; therefore, it could be a CV risk biomarker. Nevertheless there is a need for further confirmation in longitudinal studies

INTRODUCCIÓN: la proteína ABCA1 juega un papel principal en el transporte reverso del colesterol, promoviendo su eliminación y la biogénesis de HDL. El polimorfismo de un solo nucleótido (SNP) R1587K (rs2230808) del gen ABCA1 se ha asociado con dislipidemias. OBJETIVO: investigar la relación de los genotipos del SNP R1587K con el riesgo cardiovascular (CV), el síndrome metabólico (SM), el perfil de lípidos, la actividad de paraoxonasa 1 (PON1) y los anticuerpos contra las LDL oxidadas (anti-oxLDL). MÉTODOS: se realizó un estudio transversal con 57 adultos del norte de México que reportaron no tener enfermedades diagnosticadas. El SNP R1587K del gen ABCA1 se detectó a través de PCR en tiempo real (qPCR) usando sondas TaqMan para discriminación alélica. Para evaluar la asociación del SNP R1587K con el SM y determinados parámetros clínicos se determinaron el perfil de lípidos, los niveles de glucosa e insulina, la actividad y concentración de PON1, los anticuerpos anti-oxLDL, los parámetros antropométricos y de composición corporal, y el cálculo del índice aterogénico en plasma. RESULTADOS: los resultados mostraron mayores niveles de triglicéridos en los portadores del genotipo RR + KK que en los portadores de RR (p = 0,031). Se observó una asociación entre el genotipo RK + KK y la presencia de SM (OR = 4,566, IC 95% = 1,386-14,92, p = 0,010) y una tendencia hacia un mayor riesgo cardiovascular (OR = 3,317, IC 95% = 0,910-8,611, p = 0,069) al compararlos con los portadores de RR. No se encontraron diferencias en los niveles de HDL-C, la actividad y concentración de PON1 y los anti-oxLDL entre los genotipos R1587K. CONCLUSIONES: el SNP R1587K del gen ABCA1 se encuentra presente en la población del norte de México y el genotipo RK + KK se asocia con el SM y concentraciones elevadas de triglicéridos, por lo que este SNP podría ser un biomarcador de riesgo cardiovascular. Sin embargo, se necesita confirmación a través de estudios longitudinales

Transportadores ABC y resistencia a fármacos en la epilepsia: plausibilidad biológica, farmacogenética y medicina de precisión / ABC transporters and drug resistance in epilepsy: biological plausibility, pharmacogenetics and precision medicine

Introducción: Un mecanismo plausible que puede contribuir a la resistencia a fármacos en la epilepsia es la falta de llegada de los fármacos al tejido encefálico, causado por cambios en la actividad de los transportadores ABC. El principal argumento a favor de esta hipótesis es que la resistencia ocurre frente a una gran variedad de fármacos antiepilépticos con distintos mecanismos de acción, lo que sugiere un fenómeno subyacente no específico que limita la efectividad de los tratamientos farmacológicos. Desarrollo: Se realiza una revisión bibliográfica de los transportadores ABC, su papel en la fisiología normal de la barrera hematoencefálica y en la resistencia a fármacos en la epilepsia, tanto en estudios en humanos como en modelos animales. Se revisan además los estudios de variantes genéticas en los genes ABCB1 y ABCC2, que codifican para estos transportadores, y los recientes estudios genómicos en la epilepsia y patologías afines, discutiendo sus alcances y limitaciones. Conclusiones: Hasta ahora, la asociación de variantes genéticas de transportadores ABC con la resistencia a fármacos anticonvulsionantes sigue siendo materia de debate. Se espera que la creciente masificación y accesibilidad a tecnologías de secuenciación modernas permitan establecer marcadores genéticos que otorguen una aproximación de medicina de precisión para el tratamiento de la epilepsia

Introduction: A plausible mechanism that may contribute to drug resistance in epilepsy is the failure of drugs to reach the brain tissue, caused by changes in the activity of ABC transporters. The main argument in favour of this hypothesis is that resistance occurs against a wide variety of antiepileptic drugs with different mechanisms of action, suggesting a non-specific underlying phenomenon that limits the effectiveness of drug treatments. Development: A review of the literature on ABC transporters, their role in the normal physiology of the blood-brain barrier and drug resistance in epilepsy, both in human studies and in animal models, is conducted. Studies of genetic variants in the ABCB1 and ABCC2 genes, which code for these transporters, and recent genomic studies in epilepsy and related pathologies are also reviewed, followed by a discussion of their scope and limitations. Conclusions: To date, the association of genetic variants of ABC transporters with resistance to anticonvulsant drugs remains a matter of debate. The increasingly widespread use and accessibility of modern sequencing technologies is expected to allow the establishment of genetic markers that provide a precision medicine based approach to the treatment of epilepsy

Farmacogenómica: la medicina personalizada / Pharmacogenomic: the personalized medicine

El principal objetivo de la farmacogenómica (PGx) es definir un tratamiento farmacológico individualizado basado en el perfil genético de cada paciente, convirtiendo el paradigma clásico de tratamiento clínico centrado en la enfermedad en un nuevo enfoque, la medicina personalizada. Los polimorfismos genéticos pueden modificar la expresión y la función de las enzimas y las proteínas involucradas en la farmacocinética y la farmacodinámica de los fármacos. Así, la presencia de variantes alélicas permite predecir la respuesta farmacológica para garantizar la eficacia y la seguridad del tratamiento. Para la aplicación clínica de la PGx mediante la identificación de dichas variantes existen actualmente 2 planteamientos diferentes: el análisis de genes candidatos y los estudios de asociación genómica. La implementación clínica de la PGx mejora la eficacia, la seguridad y la relación costo-efectividad de los tratamientos; sin embargo, se ha ralentizado debido a una serie de barreras que se revisarán en este trabajo, así como sus posibles soluciones

The main objective of pharmacogenomics (PGx) is defining an individualized pharmacological treatment based on the genetic profile of each patient. Thus, the classical paradigm of clinical treatment focused on the disease is becoming a new approach, Personalized Medicine. The expression and function of enzymes and proteins involved in the drug pharmacokinetics and pharmacodynamics can be modified by genetic polymorphisms. Thereby, the presence of allelic variants allows predicting the pharmacological response guaranteeing the treatment efficacy and safety. Nowadays, two different approaches have been described for the clinical application of PGx by these variants identification: candidate gene analysis and genome wide association studies. Despite improving the effectiveness, safety and cost-effectiveness of treatments, the PGx clinical implementation has slowed down due to a series of barriers that will be reviewed in this work, as well as their possible solutions

ABCA3 Deficiency in a Newborn with Respiratory Failure / Deficiencia de ABCA3 en un recién nacido con insuficiencia respiratoria

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Changes in the activity of some metabolic enzymes in the heart of SHR rat incurred by transgenic expression of CD36

Hypertension, dyslipidemia, and insulin resistance in the spontaneously hypertensive rat (SHR) can be alleviated by rescuing CD36 fatty acid translocase. The present study investigated whether transgenic rescue of CD36 in SHR could affect mitochondrial function and activity of selected metabolic enzymes in the heart. These analyses were conducted on ventricular preparations derived from SHR and from transgenic strain SHR-Cd36 that expresses a functional wild-type CD36. Our respirometric measurements revealed that mitochondria isolated from the left ventricles exhibited two times higher respiratory activity than those isolated from the right ventricles. Whereas, we did not observe any significant changes in functioning of the mitochondrial respiratory system between both rat strains, enzyme activities of total hexokinase, and both mitochondrial and total malate dehydrogenase were markedly decreased in the left ventricles of transgenic rats, compared to SHR. We also detected downregulated expression of the succinate dehydrogenase subunit SdhB (complex II) and 70 kDa peroxisomal membrane protein in the left ventricles of SHR-Cd36. These data indicate that CD36 may affect in a unique fashion metabolic substrate flexibility of the left and right ventricles

Interacciones farmacocinéticas de telaprevir con otros fármacos / Pharmacokinetic interactions of telaprevir with other drugs

Con la introducción de telaprevir, un nuevo antiviral de acción directa frente al virus de la hepatitis C (VHC), sustrato e inhibidor de la isoenzima CYP3A del citocromo P450, la valoración de las interacciones medicamentosas se ha convertido en un elemento de importancia capital en la evaluación de los pacientes que realizan tratamiento para la hepatitis C. Hay que tener presente que durante el tratamiento de esta infección, muchos pacientes necesitan tomar otros medicamentos para mitigar los efectos adversos de los fármacos anti-VHC y para el control de otras comorbilidades. Además, los pacientes coinfectados por el VHC y el virus de la inmunodeficiencia humana necesitan, en su inmensa mayoría, tomar antirretrovirales durante el tratamiento de la hepatitis C. Es muy importante, por lo tanto, conocer las propiedades farmacocinéticas de los antivirales de acción directa frente al VHC, así como sus potenciales interacciones medicamentosas. En este capítulo se revisa la información disponible hasta la fecha sobre las interacciones de telaprevir con otros fármacos y se dan unas recomendaciones para la práctica clínica diaria

Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice

Recombinant human endostatin could eliminate the pro-angiogenesis priority of SP cells sorted from non-small cell lung cancer cells

PURPOSE: To ascertain the biologic significance of lung cancer Side population (SP) cells, which represent putative cancer stem cells (CSC) in the absence of consensus biomarkers for tumor-specific CSC. MATERIALS AND METHODS: We sorted and analyzed the angiogenic features of SP cells, isolated from tumor cell lines based on the exclusion of the DNA dye Hoechst 33342, from the NSCLC cell lines A549 and H460. RESULTS: Compared with non-SP cells, mRNA of vascular endothelial growth factor (VEGF)-A, VEGF-B, angiopoietin (ang)-1, ang-2, fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8) were over-expressed in SP cells accompanied by over-expression of ABCG2 and MDR1 mRNA. The supernatant of cultured SP cells could significantly induce migration of human umbilical vein endothelial cells, while recombinant human endostatin (Endostar 25(®)) could inhibit the migration. CONCLUSIONS: This study revealed that the NSCLC SP cells might represent CSCs and possess pro-angiogenic properties, and antiangiogenesis represent a potential therapy (AU)

Transporters in the intestine limiting drug and toxin absorption

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The pharmacokinetic behaviour of drugs strongly depends on transporters inintestine and liver. The extent of absorption in the intestine depends on diffusionacross the mucosa as well as transporter-mediated uptake across the apical membraneof enterocytes. Efflux pumps in this membrane may strongly reduce the extent of netuptake. These efflux pumps are ATP-binding cassette (ABC) transporters which arealso expressed in the apical membrane of the hepatocyte were they mediate excretioninto bile. This combined activity strongly determines whether drugs have access tothe systemic circulation (AU)

Colestasis infantil y transportadores biliares / Childhood cholestasis and bile transporters

La identificación de los sistemas de transporte involucrados en la secreción de la bilis y de los genes que los codifican ha permitido conocer la etiología en la mayoría de los niños afectos de colestasis intrahepática familiar. Las mutaciones en ATP8B1 ocasionan un defecto de FIC1, una flipasa de aminofosfolípidos, y causan un espectro de enfermedad variable, desde colestasis intrahepática progresiva a colestasis benigna recurrente, debido a alteraciones en la composición lipídica de las membranas y a una expresión disminuida del factor nuclear FXR. Las mutaciones en ABCB11 originan el defecto de la bomba canalicular de sales biliares BSEP, con manifestaciones clínicas tempranas y evolución a insuficiencia hepatocelular en la infancia. Las mutaciones en ABCB4 causan una alteración en el transportador de fosfolípido a bilis MDR3, y un espectro de enfermedad variable, con daño ductal progresivo a cirrosis en niños, o con litiasis biliar, colestasis gravídica o cirrosis tardía en adultos

Identification of the transport systems involved in bile secretion and of the genes codifying these systems has allowed the etiology of familial intrahepatic cholestasis to be determined in most affected children. Mutations in ATP8B1 cause a defect in FIC1, an aminophospholipid flipase, and give rise to a variable spectrum of disease, ranging from progressive intrahepatic cholestasis to benign recurrent cholestasis, due to alterations in the lipid composition of the membranes and decreased expression of the nuclear factor FXR. Mutations in ABCB11 cause a defect of the canalicular bile salt export pump (BSEP), with early clinical manifestations and progression to hepatocellular failure in childhood. Mutations in ABCB4 cause an alteration in the MDR3 phospholipid transporter, and a variable spectrum of disease from progressive ductal injury to cirrhosis in children, and gallstones, cholestasis of pregnancy, or late cirrhosis in adults

ABC transporters in the protozoan parasite Leishmania

ATP-binding cassette (ABC) transporters constitute one of the biggest and most conserved protein families in the evolutionary scale. Many of them are of enormous clinical relevance, due to their relationship with genetic diseases and drug resistance during the treatment of cancer and infectious diseases. Leishmaniasis is a major and globally widespread group of parasitic diseases, whose treatment has been complicated by the expansion of resistance to conventional drugs. Here, we review the current knowledge about ABC transporters in Leishmania spp, with special attention to their relationship with the drug-resistance phenotype (AU)

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