Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32608, USA.
Int J Mol Sci. 2023 Jun 16;24(12):10222. doi: 10.3390/ijms241210222.
Doxorubicin (DOX) is a highly effective chemotherapy agent prescribed for cancer treatment. However, the clinical use of DOX is limited due to off-target toxicity in healthy tissues. In this regard, hepatic and renal metabolic clearance results in DOX accumulation within these organ systems. Within the liver and kidneys, DOX causes inflammation and oxidative stress, which promotes cytotoxic cellular signaling. While there is currently no standard of care to treat DOX hepatic- and nephrotoxicity, endurance exercise preconditioning may be an effective intervention to prevent elevations in liver alanine transaminase (ALT) and aspartate aminotransferase (AST) and to improve kidney creatinine clearance. To determine whether exercise preconditioning is sufficient to reduce liver and kidney toxicity resulting from acute exposure to DOX chemotherapy treatment, male and female Sprague-Dawley rats remained sedentary or were exercise trained prior to saline or DOX exposure. Our findings demonstrate that DOX treatment elevated AST and AST/ALT in male rats, with no effects of exercise preconditioning to prevent these increases. We also showed increased plasma markers of renin-angiotensin-aldosterone system (RAAS) activation and urine markers of proteinuria and proximal tubule damage, with male rats revealing greater differences compared to females. Exercise preconditioning showed improved urine creatinine clearance and reduced cystatin c in males, while females had reduced plasma angiotensin II (AngII) levels. Our results demonstrate both tissue- and sex-specific responses related to the effects of exercise preconditioning and DOX treatment on markers of liver and kidney toxicity.
多柔比星（DOX）是一种高效的化疗药物，用于癌症治疗。然而，由于其在健康组织中的脱靶毒性，临床应用受到限制。在这方面，肝和肾的代谢清除导致 DOX 在这些器官系统中积累。在肝脏和肾脏中，DOX 会引起炎症和氧化应激，从而促进细胞毒性信号传导。虽然目前尚无治疗 DOX 肝毒性和肾毒性的标准方法，但耐力运动预处理可能是一种有效的干预措施，可以预防肝丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高，并改善肾脏肌酐清除率。为了确定运动预处理是否足以减轻急性接触 DOX 化疗治疗引起的肝和肾毒性，雄性和雌性 Sprague-Dawley 大鼠在接受盐水或 DOX 暴露之前保持久坐或进行运动训练。我们的研究结果表明，DOX 治疗使雄性大鼠的 AST 和 AST/ALT 升高，而运动预处理并不能预防这些升高。我们还显示了肾素-血管紧张素-醛固酮系统 (RAAS) 激活的血浆标志物和蛋白尿和近端肾小管损伤的尿液标志物增加，雄性大鼠与雌性大鼠相比显示出更大的差异。运动预处理可改善雄性大鼠的尿肌酐清除率并降低胱抑素 c，而雌性大鼠的血浆血管紧张素 II (AngII) 水平降低。我们的研究结果表明，运动预处理和 DOX 治疗对肝毒性和肾毒性标志物的影响与组织和性别特异性反应有关。
