Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
Monash Proteomics and Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
Mol Pharm. 2024 Apr 1;21(4):1756-1767. doi: 10.1021/acs.molpharmaceut.3c01089. Epub 2024 Feb 28.
Amyotrophic lateral sclerosis (ALS) is characterized by death and dysfunction of motor neurons that result in a rapidly progressing loss of motor function. While there are some data on alterations at the blood-brain barrier (BBB) in ALS and their potential impact on CNS trafficking of drugs, little is reported on the impact of this disease on the expression of drug-handling proteins in the small intestine and liver. This may impact the dosing of the many medicines that individuals with ALS are prescribed. In the present study, a proteomic evaluation was performed on small intestine and liver samples from postnatal day 120 SOD1 mice (a model of familial ALS that harbors a human mutant form of superoxide dismutase 1) and wild-type (WT) littermates ( = 7/genotype/sex). Untargeted, quantitative proteomics was undertaken using either label-based [tandem mass tag (TMT)] or label-free [data-independent acquisition (DIA)] acquisition strategies on high-resolution mass spectrometric instrumentation. Copper chaperone for superoxide dismutase (CCS) was significantly higher in SOD1 samples compared to the WT samples for both sexes and tissues, therefore representing a potential biomarker for ALS in this mouse model. Relative to WT mice, male SOD1 mice had significantly different proteins ( < 0.05, |fold-change|>1.2) in the small intestine (male 22, female 1) and liver (male 140, female 3). This included an up-regulation of intestinal transporters for dietary glucose [solute carrier (SLC) SLC5A1] and cholesterol (Niemann-Pick c1-like 1), as well as for several drugs (e.g., SLC15A1), in the male SOD1 mice. There was both an up-regulation (e.g., SLCO2A1) and down-regulation (ammonium transporter rh type b) of transporters in the male SOD1 liver. In addition, there was both an up-regulation (e.g., phosphoenolpyruvate carboxykinase) and down-regulation (e.g., carboxylesterase 1) of metabolizing enzymes in the male SOD1 liver. This proteomic data set identified male-specific changes to key small intestinal and hepatic transporters and metabolizing enzymes that may have important implications for the bioavailability of nutrients and drugs in individuals with ALS.
肌萎缩侧索硬化症（ALS）的特征是运动神经元的死亡和功能障碍，导致运动功能迅速恶化。虽然有一些关于 ALS 中血脑屏障（BBB）改变及其对中枢神经系统药物转运潜在影响的数据，但关于这种疾病对小肠和肝脏中药物处理蛋白表达的影响却鲜有报道。这可能会影响 ALS 患者所开处方的许多药物的剂量。在本研究中，对 120 天大的 SOD1 小鼠（携带超氧化物歧化酶 1 人突变体的家族性 ALS 模型）和野生型（WT）同窝仔鼠（ = 7/基因型/性别）的小肠和肝脏样本进行了蛋白质组学评估。使用基于标签（串联质量标签（TMT））或无标签（数据独立采集（DIA））的定量蛋白质组学策略，在高分辨率质谱仪上进行了非靶向、定量蛋白质组学分析。铜伴侣超氧化物歧化酶（CCS）在 SOD1 样本中明显高于 WT 样本，无论是在两性还是组织中，因此代表了这种小鼠模型中 ALS 的一个潜在生物标志物。与 WT 小鼠相比，雄性 SOD1 小鼠的小肠（雄性 22，雌性 1）和肝脏（雄性 140，雌性 3）中蛋白质有明显差异（ < 0.05，|fold-change|>1.2）。这包括肠道对膳食葡萄糖[溶质载体（SLC）SLC5A1]和胆固醇（尼曼-匹克 C1 样 1）的转运体以及几种药物（例如 SLC15A1）的上调。雄性 SOD1 肝脏中的转运体既有上调（例如 SLCO2A1）也有下调（铵转运蛋白 rh 型 b）。此外，雄性 SOD1 肝脏中代谢酶既有上调（例如磷酸烯醇丙酮酸羧激酶）也有下调（例如羧酸酯酶 1）。该蛋白质组数据集确定了关键的小肠和肝脏转运体和代谢酶在雄性中的特定变化，这可能对 ALS 患者的营养物质和药物的生物利用度有重要影响。
