Differences in mRNA Expression of Selected Cytochrome P450, Transporters and Nuclear Receptors Among Various Rat Models of Metabolic Syndrome

IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Jan Soukop, Zuzana Rácová, Ludmila Kazdová, Iveta Zapletalová, Martin Poruba, Hana Malínská, Martina Hüttl, Irena Marková, Kristýna Nováková, Rostislav Večeřa
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Abstract

Metabolic syndrome (MetS) is a cluster of risk factors that increase the likelihood of developing cardiovascular, metabolic and other diseases. The pharmacological management of MetS often involves polypharmacy, making it essential to understand how drug-metabolising enzymes, transporters, transcription factors and other proteins involved are affected under different metabolic conditions. This study investigated the relative mRNA expression of key hepatic and intestinal genes involved in drug metabolism, including Cyp1a2, Cyp3a23, Cyp2d1, Cyp2c11, Cyp2c6, Cyp2e1, Cyp7a1, Cyp2b1, Cyp2a1, Abcg5, Abcg8, Abcb1, Nr1i3, Nr1i2, Ahr, Gsta1 and Comt, in four nonobese rat models of MetS: hereditary hypertriglyceridaemic (HHTg), spontaneously hypertensive rat (SHR), SHR expressing transgenic human C-reactive protein (SHR-CRP), and bilaterally ovariectomised Wistar (W-OVX), compared to Wistar controls. Gene expression was quantified by RT–PCR with data normalised using the ΔΔCt method. Between the models studied, measurements showed significant differences in the liver. The upregulation of Cyp2c6 and Cyp3a23 was observed only in SHR; upregulated Cyp2d1 was found in SHR as well as in HHTg rats. The downregulated Cyp1a2 was measured in a condition of hypertriglyceridemia, postmenopause or hypertension. These findings highlight model-specific alterations in gene expression that may affect drug metabolism and interactions. The HHTg may be, in particular, a suitable model for preclinical studies focusing on intestinal drug–drug interactions in MetS-related conditions.

Abstract Image

不同代谢综合征大鼠模型中细胞色素P450、转运体和核受体mRNA表达的差异
代谢综合征(MetS)是一组增加患心血管、代谢和其他疾病可能性的危险因素。MetS的药理学管理通常涉及多种药物,因此了解药物代谢酶、转运体、转录因子和其他相关蛋白质在不同代谢条件下如何受到影响至关重要。本研究研究了四种非肥胖大鼠MetS模型中参与药物代谢的关键肝脏和肠道基因Cyp1a2、Cyp3a23、Cyp2d1、Cyp2c11、Cyp2c6、Cyp2e1、Cyp7a1、Cyp2b1、Cyp2a1、Abcg5、Abcg8、Abcb1、Nr1i3、Nr1i2、Ahr、Gsta1和Comt的相对mRNA表达情况:遗传性高甘油三酯血症(HHTg),自发性高血压大鼠(SHR),表达转基因人c反应蛋白(SHR- crp)的SHR,以及双侧卵巢切除的Wistar (W-OVX)。采用RT-PCR定量分析基因表达,数据归一化方法为ΔΔCt。在研究的模型之间,测量结果显示肝脏有显著差异。Cyp2c6和Cyp3a23仅在SHR中表达上调;在SHR和HHTg大鼠中发现Cyp2d1表达上调。Cyp1a2下调是在高甘油三酯血症、绝经后或高血压的情况下测量的。这些发现强调了模型特异性基因表达的改变可能影响药物代谢和相互作用。特别是,HHTg可能是一个适合于临床前研究的模型,重点是肠道药物-药物相互作用。
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来源期刊
CiteScore
5.60
自引率
6.50%
发文量
126
审稿时长
1 months
期刊介绍: Basic & Clinical Pharmacology and Toxicology is an independent journal, publishing original scientific research in all fields of toxicology, basic and clinical pharmacology. This includes experimental animal pharmacology and toxicology and molecular (-genetic), biochemical and cellular pharmacology and toxicology. It also includes all aspects of clinical pharmacology: pharmacokinetics, pharmacodynamics, therapeutic drug monitoring, drug/drug interactions, pharmacogenetics/-genomics, pharmacoepidemiology, pharmacovigilance, pharmacoeconomics, randomized controlled clinical trials and rational pharmacotherapy. For all compounds used in the studies, the chemical constitution and composition should be known, also for natural compounds.
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