Domijan Ana-Marija, Zeljezić Davor, Milić Mirta, Peraica Maja
Unit of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska c. 2, 10000 Zagreb, Croatia.
Toxicology. 2007 Apr 11;232(3):163-9. doi: 10.1016/j.tox.2007.01.007. Epub 2007 Jan 14.
Fumonisin B(1) (FB(1)) is a carcinogenic mycotoxin involved in several animal diseases and assumed to be involved in the etiology of some human tumors. FB(1) disturbs the metabolism of sphinganine (Sa) and sphingosine (So), increasing the ratio of their concentrations (Sa/So). FB(1) is mutagenic in cell cultures, but the mechanism of its genotoxicity is not understood. The aim of this study was to see whether DNA lesions in kidney and liver cells of rats treated with FB(1) were related to the changes in the oxidative status or to the disturbance of the sphingolipid metabolism. Male Wistar rats were receiving either FB(1) (0.5 mg/kg b.w./day, i.p. for 2 or 7 days) or solvent only and were sacrificed 24 h after the last treatment. The ratio of Sa and So concentrations and parameters of oxidative status (catalytic activity of catalase and the concentrations of protein carbonyls and malondialdehyde, MDA) were measured in plasma and liver and kidney homogenates, while DNA damage was measured in liver and kidney using the comet assay. In plasma and liver and kidney homogenates catalase activity and the concentrations of protein carbonyls and MDA were not affected by the 2-day treatment with FB(1), but the ratio of Sa and So in plasma and liver and kidney homogenates was significantly higher than in controls (0.99+/-0.27 versus 0.38+/-0.08, 1.05+/-0.12 versus 0.59+/-0.09 and 4.51+/-0.51 versus 0.54+/-0.17, respectively) (p<0.05). After the 2-day treatment, the tail length and tail intensity measured with the comet assay in the liver homogenate did not change, while in the kidney homogenate, the difference between the treated and control animals was significant in both the tail length (26.4+/-0.7 microm versus 14.6+/-0.1 microm) and tail intensity (8.0+/-0.4% versus 1.7+/-0.02% DNA) (p<0.05). After the 7-day treatment all measured parameters significantly differed from controls (p<0.05). This study showed that FB(1) causes DNA lesions in the kidney of experimental animals before affecting the catalytic activity of catalase and the concentration of protein carbonyls and MDA. The ratio of Sa and So significantly increases in all tissues already after 2-day treatment thus indicating that the metabolism of sphingolipids may have an important role in the DNA damage caused by FB(1).
伏马菌素B1(FB1)是一种致癌霉菌毒素,与多种动物疾病有关,并且被认为与某些人类肿瘤的病因有关。FB1会干扰鞘氨醇(Sa)和鞘氨醇(So)的代谢,增加它们浓度的比值(Sa/So)。FB1在细胞培养中具有致突变性,但其遗传毒性机制尚不清楚。本研究的目的是观察用FB1处理的大鼠肾和肝细胞中的DNA损伤是否与氧化状态的变化或鞘脂代谢紊乱有关。雄性Wistar大鼠分别接受FB1(0.5mg/kg体重/天,腹腔注射2或7天)或仅溶剂处理,并在最后一次处理后24小时处死。在血浆、肝和肾匀浆中测量Sa和So浓度的比值以及氧化状态参数(过氧化氢酶的催化活性、蛋白质羰基和丙二醛(MDA)的浓度),而使用彗星试验在肝和肾中测量DNA损伤。在血浆、肝和肾匀浆中,过氧化氢酶活性、蛋白质羰基和MDA的浓度不受FB1 2天处理的影响,但血浆、肝和肾匀浆中Sa和So的比值显著高于对照组(分别为0.99±0.27对0.38±0.08、1.05±0.12对0.59±0.09和4.51±0.51对0.54±0.17)(p<0.05)。2天处理后,用彗星试验在肝匀浆中测量的尾长和尾强度没有变化,而在肾匀浆中,处理组和对照组动物在尾长(26.4±0.7微米对14.6±0.1微米)和尾强度(8.0±0.4%对1.7±0.02%DNA)方面的差异均具有统计学意义(p<0.05)。7天处理后,所有测量参数与对照组均有显著差异(p<0.05)。本研究表明,FB1在影响过氧化氢酶的催化活性、蛋白质羰基和MDA的浓度之前,就会导致实验动物肾脏中的DNA损伤。仅2天处理后,所有组织中Sa和So的比值就显著增加,这表明鞘脂代谢可能在FB1引起的DNA损伤中起重要作用。