Effect of Disease Pathologies on Transporter Expression and Function

Sun

Journal of Pharmacy and Pharmacology

et al. 2018

The molecular mechanism of decreased expression of Oat1 and Oat3 was achieved through activating p53, and then increasing the expression of Bax and Caspase-3 and down regulating Bcl-2 in AKI rats. On this basis, the cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration of cefdinir was remarkably increased in AKI rats. However, the pharmacokinetic changes of cefditoren were not observed. Accordingly, cephalosporin antibiotics such as cefditoren should be firstly selected for the treatment in patients with AKI in clinic.

Section: Discussionmentioning

confidence: 99%

“…In addition, the expression and function of renal transporters would be changed under the condition of AKI. However, the current research on this aspect was extremely limited and it still needed further investigation …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Sun

Journal of Pharmacy and Pharmacology

et al. 2018

“…It is responsible for excreting soluble metabolic waste products and pharmaceutical drugs, maintaining normal biological functions, and secreting hormones and enzymes [9][10][11][12]57]. Numerous global gene expression studies involving diseased kidney have identified sex differences in several functions performed by the kidney, such as glomerular filtration, tubular secretion, and tubular reabsorption [6,58].…”

Section: Discussionmentioning

confidence: 99%

Epigenome-Wide Association (DNA Methylation) Study of Sex Differences in Normal Human Kidney

Joseph¹,

George²,

Green-Knox³

et al. 2017

J Drug Metab Toxicol

Studies have identified epigenetic sex differences in several human tissues and have implicated epigenetic factors in the regulation of tissue-specific expression. Studies have also shown that women and men respond differently to various drugs, thereby influencing the pharmacokinetics, pharmacodynamics, adverse reactions, efficacy, and safety of a drug. Using Illumina Human Methylation450 BeadChip kit, we investigated the influence of sex on DNA methylation patterns in normal human kidneys (16 females and 15 males). We then related the methylome to mRNA expression levels in kidney structure/function and Drug Metabolizing Enzyme and Transporter (DMET) genes (32 females and 59 males). Our findings indicate that 429 methylated sites on autosomal chromosomes had significant sex-specific differences in the normal human kidney. Methylated sites in/near regions associated with DMET genes or with genes involved in renal structure/function and disease were identified for subsequent analysis. Validation of 2 DMETs genes (POR and ABCA3) and 2 renal structure/function/disease genes (LAMA5 and PLAT) exhibited significant sex-specific differences in mRNA expression. Our results highlight sitespecific sexual dimorphisms (epigenetic-based) in normal human kidney. Importantly, we provide a reference methylome for normal human kidney, which may be utilized to improve our understanding of renal disease and assessing the overall safety and effectiveness of a drug in the kidney.

“…Nossos resultados estão em concordância com a literatura que indica a manutenção ou aumento da expressão de MRP2 no carcinoma hepatocelular. (135,137,(154)(155)(156)(157) A ausência de variação da expressão de MRP2 em relação ao número, tamanho dos nódulos, padrão arquitetural (inclusive os sólidos), e grau de diferenciação (inclusive os menos diferenciados) de CHC sugere que a proteína MRP2 apresenta-se altamente expressa no CHC independentemente das variáveis anatomopatológicas analisadas. Desta forma, a escassez de informações e a presença de resultados divergentes sobre a avaliação da expressão desta proteína nos adenocarcinomas de ductos biliares conduzem a necessidade de ampliação da investigação desta proteína transportadora nos colangiocarcinomas.…”

Section: Discussão 154unclassified

“…A principal função desta proteína ABC está relacionada ao transporte de compostos orgânicos e sais biliares conjugados bivalentes, podendo estar super expressa em condições colestáticas. (34,157) No presente estudo, apenas 14 (17,5%) dos 80 CHC avaliados mostraram-reação positiva com o anticorpo MRP3 (DTX1), exibindo distribuição basolateral em mais de 10% dos hepatócitos tumorais.…”

Section: -Mrp3 -Proteína 3 Associada à Resistência à Múltiplas Drogasunclassified

Avaliação da expressão imuno-histoquímica de proteínas transportadoras biliares em carcinoma hepatocelular e em colangiocarcinoma

Cirqueira¹

________________________________________________________________RESUMOos casos de colangiocarcinoma foram negativos para a avaliação da expressão de MDR3, diferindo significativamente em relação a expressão de CEA (P=0,001), mas não em comparação a Hep-par-1 e Arginase-1 (P>0,05). As reações IHQ para detecção de MRP2 exibiram positividade canalicular em 92,3% dos casos de CHC e em 96,3% nos casos de CC. A detecção da alta expressão de MRP2 no CHC foi constante (P>0,05) em comparação ao tamanho, número dos nódulos, padrão arquitetural e grau histológico de diferenciação de CHC assim como, também não apresentou associação (P>0,05) com a localização, padrão de crescimento e grau de diferenciação do CC. A reação IHQ para MRP3 resultou positiva em 15/80 casos de CH (18,8%). A reatividade IHQ para MRP foi detectada em 24/54 (44,5%) de CC. Diferente dos transportadores descritos acima, a expressão de MRP3 foi preferencialmente basolateral. A positividade para MRP3 não variou (P>0,05) em relação ao número, tamanho dos nódulos, padrão arquitetural (inclusive os sólidos), e grau de diferenciação (inclusive os menos diferenciados). A proteína MRP3 esteve expressa regularmente (P>0,05) em todos os casos de CC, apresentando-se reduzida apenas no subtipo histológico ductular (P=0,023). Em conclusão, o excelente contraste de reação, a frequência razoavelmente alta de positividade de CHC e a plena negatividade de CC para BSEP levam-nos a recomendar a introdução do anticorpo monoclonal anti-BSEP no painel adotado para o diagnóstico diferencial dessas duas neoplasias. A alta expressão de MRP2 no CHC e no CC é conservada independentemente dos parâmetros anatomopatológicos avaliados. A expressão do transportador MRP3 mostrou variação dentre os subtipos histológicos de CC, aspecto que torna promissoras pesquisas futuras para avaliação mais detalhada da expressão deste marcador nos colangiocarcinomas. The assessment of biliary transporters, previously restricted to the physiology and pathophysiology of cholestasis, has recently included hepato-biliary neoplasms. The present study aimed to characterize the expression of BSEP, MDR3, MRP2 and MRP3 biliary transport proteins in retrospectively collected samples from 80 cases of autopsy of hepatocellular carcinoma (HCC) and 56 cases of surgical resection of cholangiocarcinoma (CC). Representative areas of the neoplasms were organized into tissue microarrays and submitted to immunohistochemical (IHC) reaction with polyclonal antibody anti-BSEP (HPA019035) and monoclonal antibodies anti-BSEP (F6), MDR3 (P3 II-26), MRP2 (M2 III-6) and MRP3 (DTX-1). Signal amplification was achieved with a short polymer system conjugated to peroxidase. The comparison between the positivity of the immunohistochemical reactions for each antibody and the pathological variables was performed using the Pearson chi-square test or the Fisher's exact test. The performance of antibodies which provided a better distinction of the positive signal vs nonspecific background staining and yield better discrimination between...