Kuhn Michael, Hassan Reham, González Daniela, Myllys Maiju, Hobloss Zaynab, Degen Gisela H, Humpf Hans-Ulrich, Hengstler Jan G, Cramer Benedikt, Ghallab Ahmed
Institute of Food Chemistry, University Münster, Corrensstr. 45, 48149, Münster, Germany.
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany.
Mycotoxin Res. 2024 Aug;40(3):433-445. doi: 10.1007/s12550-024-00538-1. Epub 2024 May 14.
Ochratoxin A (OTA) is known to be strongly bound to serum albumin, but it remains unknown how albumin affects its metabolism and kinetics. To close this gap, we used a mouse model, where heterozygous albumin deletion reduces serum albumin to concentrations similar to hypoalbuminemic patients and completely eliminates albumin by a homozygous knockout. OTA and its potential metabolites (OTα, 4-OH-OTA, 7'-OH-OTA, OTHQ, OP-OTA, OTB-GSH, OTB-NAC, OTB) were time-dependently analyzed in plasma, bile, and urine by LC-MS/MS and were compared to previously published hepatotoxicity and nephrotoxicity data. Homozygous albumin deletion strongly accelerated plasma clearance as well as biliary and urinary excretion of the parent compound and its hydroxylation products. Decreasing albumin in mice by the heterozygous and even more by the homozygous knockout leads to an increase in the parent compound in urine which corresponded to increased nephrotoxicity. The role of albumin in OTA-induced hepatotoxicity is more complex, since heterozygous but not homozygous nor wild-type mice showed a strong biliary increase in the toxic open lactone OP-OTA. Correspondingly, OTA-induced hepatotoxicity was higher in heterozygous than in wild-type and homozygous animals. We present evidence that albumin-mediated retention of OTA in hepatocytes is required for formation of the toxic OP-OTA, while complete albumin elimination leads to rapid biliary clearance of OTA from hepatocytes with less formation of OP-OTA. In conclusion, albumin has a strong influence on metabolism and toxicity of OTA. In hypoalbuminemia, the parent OTA is associated with increased nephrotoxicity and the open lactone with increased hepatotoxicity.
已知赭曲霉毒素A（OTA）与血清白蛋白紧密结合，但白蛋白如何影响其代谢和动力学仍不清楚。为了填补这一空白，我们使用了一种小鼠模型，杂合子白蛋白缺失会使血清白蛋白浓度降低至与低白蛋白血症患者相似的水平，而纯合子敲除则会完全消除白蛋白。通过液相色谱-串联质谱法（LC-MS/MS）对血浆、胆汁和尿液中的OTA及其潜在代谢产物（OTα、4-羟基-OTA、7'-羟基-OTA、OTHQ、OP-OTA、OTB-GSH、OTB-NAC、OTB）进行了时间依赖性分析，并与先前发表的肝毒性和肾毒性数据进行了比较。纯合子白蛋白缺失显著加速了母体化合物及其羟基化产物的血浆清除以及胆汁和尿液排泄。通过杂合子甚至纯合子敲除降低小鼠体内的白蛋白会导致尿液中母体化合物增加，这与肾毒性增加相对应。白蛋白在OTA诱导的肝毒性中的作用更为复杂，因为杂合子小鼠而非纯合子或野生型小鼠的胆汁中有毒的开放内酯OP-OTA显著增加。相应地，杂合子小鼠中OTA诱导的肝毒性高于野生型和纯合子动物。我们提供的证据表明，白蛋白介导的OTA在肝细胞中的保留是形成有毒的OP-OTA所必需的，而完全消除白蛋白会导致OTA从肝细胞中快速经胆汁清除，同时OP-OTA的形成减少。总之，白蛋白对OTA的代谢和毒性有很大影响。在低白蛋白血症中，母体OTA与肾毒性增加有关，而开放内酯与肝毒性增加有关。
