Department of Pediatrics, Faculty of Medicine, Northern Border University, Arar, Kingdom of Saudi Arabia.
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
J Appl Toxicol. 2021 Oct;41(10):1620-1633. doi: 10.1002/jat.4151. Epub 2021 Mar 19.
Amphotericin B-deoxycholate (Fungizone [FZ]) is a widely used potent antimycotic drug in spite of its nephrotoxic effect via different mechanisms. The effect of FZ on renal cell bioenergetics is not clear. The current study evaluated the effect of FZ on the bioenergetics of albino rats' isolated renal proximal tubule cells (PTCs). The cytotoxic effect of FZ on the isolated renal cells was assessed by MTT and lactate dehydrogenase (LDH) assays. The effect of FZ on the PTCs uptake (OAT1 and OCT2) and efflux (P-gp and MRP2) transporters was evaluated. Then, the effect of FZ on mitochondria was assessed by studying complexes I-IV activities, lactate assay, oxygen consumption rates (OCR), and western blotting for all mitochondrial complexes. Moreover, the effect of FZ on mitochondrial membrane fluidity (MMF) and fatty acids composition was evaluated. Additionally, the protective effect of coenzyme q10 was studied. Outcomes showed that FZ was cytotoxic to the PTCs in a concentration and time-dependent patterns. FZ significantly inhibited the studied uptake and efflux tubular transporters with inhibition of the mitochondrial complexes activities and parallel increase in lactate production and decrease in OCRs. Finally, FZ significantly reduced the expression of all mitochondrial complexes in addition to significant increase in MMF and MMFA concentration. Coenzyme Q10 was found to significantly decrease FZ-induced cytotoxicity and transporters impairment in the PTC. FZ significantly inhibits bioenergetics of PTC, which may stimulate the cascade of cell death and clinical nephrotoxicity.
两性霉素 B 去氧胆酸盐（两性霉素 B 去氧胆酸钠[FZ]）是一种广泛使用的强效抗真菌药物，尽管它具有不同机制的肾毒性。FZ 对肾细胞生物能量学的影响尚不清楚。本研究评估了 FZ 对白化大鼠分离的近端肾小管细胞（PTC）生物能量学的影响。通过 MTT 和乳酸脱氢酶（LDH）测定评估 FZ 对分离肾细胞的细胞毒性作用。评估了 FZ 对 PTC 摄取（OAT1 和 OCT2）和外排（P-糖蛋白和 MRP2）转运体的影响。然后，通过研究复合物 I-IV 活性、乳酸测定、耗氧量（OCR）和所有线粒体复合物的 Western blot 评估 FZ 对线粒体的影响。此外，评估了 FZ 对线粒体膜流动性（MMF）和脂肪酸组成的影响。还研究了辅酶 Q10 的保护作用。结果表明，FZ 以浓度和时间依赖的方式对 PTC 具有细胞毒性。FZ 显著抑制了研究中的摄取和外排管状转运体，同时抑制了线粒体复合物的活性，并平行增加了乳酸的产生，降低了 OCR。最后，FZ 除了显著增加 MMF 和 MMFA 浓度外，还显著降低了所有线粒体复合物的表达。辅酶 Q10 被发现可显著降低 FZ 诱导的 PTC 细胞毒性和转运体损伤。FZ 显著抑制 PTC 的生物能量学，这可能会刺激细胞死亡级联和临床肾毒性。
