Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2
Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2
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DOI：
10.1007/s00204-012-0807-5
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发表时间：
2012-05-01
影响因子：
6.1
通讯作者：
Glatt, Hansruedi
中科院分区：
文献类型：
--
作者：
Bauer-Marinovic, Morana;Taugner, Felicitas;Glatt, Hansruedi
5-将硫氧甲基糠醛（SMF）（丰富的美拉德产物5-羟甲基糠醛（HMF）的亲电代谢产物）腹腔内给予FVB/N小鼠。在250 mg/kg剂量下，大多数动物在5-11天后因近端小管严重损伤而死亡。在较低剂量下，反复给药，肾小管也是毒性的主要靶点，在后期发生再生和非典型增生。此外，还观察到肝毒性作用和腹膜组织浆膜炎。SMF是HMF在常规小鼠中的次要代谢产物，但HMF是人体中主要磺基转移酶（hSULT 1A 1）的优良底物。携带多拷贝hSULT 1A 12基因簇的亲代FVB/N小鼠和FVB/N-hSULT 1A 12小鼠暴露于饮用水中的HMF（0、134和536 mg/kg体重/天）12周。仅在高剂量下检测到肾毒性作用和肝细胞增殖增强。它们是温和的，并且令人惊讶的是，不受hSULT 1A 1/2表达的影响。因此，当以推注方式给药时，SMF是一种强效肾毒性物质，但当通过饮用水连续给药HMF时，SMF未达到足以产生严重毒性的水平。甚至在肝脏和肾脏中表达明显高于人类的HMF硫酸化活性的转基因小鼠中也是如此。
5-Sulphooxymethylfurfural (SMF), an electrophilic metabolite of the abundant Maillard product 5-hydroxymethylfurfural (HMF), was intraperitoneally administered to FVB/N mice. At a dosage of 250 mg/kg, most animals died after 5-11 days due to massive damage to proximal tubules. At lower dosages, administered repeatedly, tubules also were the major target of toxicity, with regeneration and atypical hyperplasia occurring at later periods. Additionally, hepatotoxic effects and serositis of peritoneal tissues were observed. SMF is a minor metabolite of HMF in conventional mice, but HMF is an excellent substrate for a major sulphotransferase (hSULT1A1) in humans. Parental FVB/N mice and FVB/N-hSULT1A1/2 mice, carrying multiple copies of the hSULT1A1/2 gene cluster, were exposed to HMF in drinking water (0, 134 and 536 mg/kg body mass/day) for 12 weeks. Nephrotoxic effects and enhanced proliferation of hepatocytes were only detected at the high dosage. They were mild and, surprisingly, unaffected by hSULT1A1/2 expression. Thus, SMF was a potent nephrotoxicant when administered as a bolus, but did not reach levels sufficient to produce serious toxicity when generated from HMF administered continuously via drinking water. This was even the case in transgenic mice expressing clearly higher HMF sulphation activity in liver and kidney than humans.