Pan Yueqing, Yang Zhuan, Wei Minlong, Gan Yulin, Liu Menghua, Zou Wei
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1023 Shatai South Road, Baiyun District, Guangzhou, 510515, Guangdong, China.
Changsha Research and Development Center on Obstetric and Gynecologic Traditional Chinese Medicine Preparation, NHC Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, No. 53 Xiangchun Road, Kaifu District, Changsha, 410008, Hunan, China.
Eur J Drug Metab Pharmacokinet. 2025 Jan;50(1):39-51. doi: 10.1007/s13318-024-00923-2. Epub 2024 Nov 10.
Hypertensive nephropathy (HN) has become one of the main causes of end-stage renal disease. Drug combination therapy is a common clinical treatment for HN. However, the impact of HN on drug-metabolizing enzymes and transporters, which may lead to drug-drug interactions (DDIs) and even trigger toxic side effects, remains unclear. The aim of this study was to investigate changes in major drug-metabolizing enzymes and transporters in the liver and kidney of HN rats to improve the scientific foundations for the clinical treatment of HN.
Spontaneously hypertensive rats (SHRs) were used as an animal HN model because their hypertension is similar to that of humans. Wistar-Kyoto rats (WKYs) were used as the control group. Body weight, blood pressure, hematoxylin-eosin (HE) staining and biochemical analysis were performed to evaluate whether the HN model was successfully constructed. Quantitative real-time polymerase chain reaction (PCR) and western blotting were used to evaluate the mRNA and protein expression of drug-metabolizing enzymes, transporters and related nuclear transcription factors.
In HN rats, the mRNA expression of the drug-metabolizing enzymes cytochrome P450 (Cyp) 2b1, Cyp2c11, Cyp3a1 and Cyp7a1 was significantly upregulated. The protein level of CYP3A1 was consistent with its mRNA expression. Interestingly, the mRNA expression of the hepatic transporters organic cation transporter (Oct) 1, Oct2, organic anion transporter (Oat) 1, Oat2, multidrug resistant protein (Mrp) 2, multidrug resistance (Mdr) 1, organic anion transporting polypeptide (Oatp) 1b2 and na+/taurocholate cotransporting polypeptide (Ntcp) was also markedly upregulated. This may be directly influenced by the upregulation of the expression of the nuclear receptors farnesoid X receptor (Fxr), pregnane X receptor (Pxr), liver X-activated receptor (Lxr) and constitutive androstane receptor (Car). In the kidney of HN rats, the mRNA level of the drug-metabolizing enzyme Cyp2b1 significantly increased, while levels of Cyp1a1, Cyp2c11, Cyp3a1 and Cyp3a2 did not significantly change. The mRNA expression of the transporters multidrug and toxin extrusion (Mate) 1 and Mrp2 was obviously increased but was markedly depressed for peptide transporters (Pept) 1 and Pept2. These changes may be related to the cross effects of Pxr, Fxr and Car in kidney.
HN pathological status can alter the expression of drug-metabolizing enzymes and transporters in the liver and kidney to varying degrees, thus affecting the disposition of substrate drugs in vivo. This suggests that to avoid potential risks, caution should be exercised when administering combination therapy for HN treatment.
高血压肾病（HN）已成为终末期肾病的主要病因之一。联合药物治疗是HN常见的临床治疗方法。然而，HN对药物代谢酶和转运体的影响尚不清楚，这可能导致药物相互作用（DDIs）甚至引发毒副作用。本研究旨在探讨HN大鼠肝脏和肾脏中主要药物代谢酶和转运体的变化，为HN的临床治疗提供科学依据。
自发性高血压大鼠（SHRs）作为动物HN模型，因其高血压情况与人类相似。Wistar-Kyoto大鼠（WKYs）作为对照组。通过体重、血压、苏木精-伊红（HE）染色和生化分析评估HN模型是否成功构建。采用定量实时聚合酶链反应（PCR）和蛋白质印迹法评估药物代谢酶、转运体及相关核转录因子的mRNA和蛋白表达。
在HN大鼠中，药物代谢酶细胞色素P450（Cyp）2b1、Cyp2c11、Cyp3a1和Cyp7a1的mRNA表达显著上调。CYP3A1的蛋白水平与其mRNA表达一致。有趣的是，肝脏转运体有机阳离子转运体（Oct）1、Oct2、有机阴离子转运体（Oat）1、Oat2、多药耐药蛋白（Mrp）2、多药耐药（Mdr）1、有机阴离子转运多肽（Oatp）1b2和钠/牛磺胆酸盐共转运多肽（Ntcp）的mRNA表达也明显上调。这可能直接受核受体法尼醇X受体（Fxr）、孕烷X受体（Pxr）、肝脏X激活受体（Lxr）和组成型雄甾烷受体（Car）表达上调的影响。在HN大鼠肾脏中，药物代谢酶Cyp2b1的mRNA水平显著升高，而Cyp1a1、Cyp2c11、Cyp3a1和Cyp3a2的水平无明显变化。转运体多药和毒素外排（Mate）1和Mrp2的mRNA表达明显增加，但肽转运体（Pept）1和Pept2的表达明显降低。这些变化可能与肾脏中Pxr、Fxr和Car的交叉作用有关。
HN病理状态可不同程度改变肝脏和肾脏中药物代谢酶和转运体的表达，从而影响体内底物药物的处置。这表明为避免潜在风险，在对HN进行联合治疗时应谨慎用药。
