Thiamine supplementation attenuated hepatocellular carcinoma in the Atp7b mouse model of Wilson's disease.
Thiamine supplementation attenuated hepatocellular carcinoma in the Atp7b mouse model of Wilson's disease.
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作者：
C. Sheline
背景威尔逊氏病是由P型Cu(2+)-ATP酶(Atp7b)基因缺陷引起的，导致Cu(2+)在肝脏中积累、毒性和肝细胞癌。 HepG2 细胞和 Atp7b 突变小鼠的肝脏暴露于有毒 Cu(2+) 会导致氧化、(KGDH) 和 (PDH) 酶抑制以及硫胺素减弱的死亡。材料和方法 使用大体形态学和多核分析证明了口服硫胺素补充剂 (2%) 对 Atp7b 动物肝脏中 Cu(2+) 积聚在 4、6、9、12、16 和 21 个月时诱导的肝细胞癌的影响。结果 16 个月大时，未经治疗的 Atp7b 动物变得濒临死亡，它们的肝脏重量是对照组的 180% 以上，并且肝脏的 75% 以上发生癌变。 16 个月时，硫胺素治疗的 Atp7b 小鼠的肝脏重量<对照组的 130%，癌性<30%，并且在 21 个月时，小鼠仍然活跃。然而，硫胺素在皮下异种移植模型中无效。结论 这项研究表明，硫胺素可能是威尔逊病诱发的肝细胞癌的预防剂。
BACKGROUND Wilson's disease is caused by a genetic defect in P-type Cu(2+)-ATPase (Atp7b), resulting in Cu(2+) accumulation in the liver, toxicity, and hepatocellular carcinoma. Exposure of HepG2 cells, and livers of Atp7b mutant mice to toxic Cu(2+) resulted in oxidation, (KGDH) and (PDH) enzyme inhibition, and death that was attenuated by thiamine. MATERIALS AND METHODS The effect of oral thiamine supplementation (2%) on hepatocellular carcinoma induced by Cu(2+) accumulation in the livers of Atp7b animals at 4, 6, 9, 12, 16, and 21 months was demonstrated using gross morphology and multi-nucleate analysis. RESULTS By 16 months of age, untreated Atp7b animals became moribund, their livers were >180% the weight of controls and >75% of their liver was cancerous. At 16 months the livers of thiamine treated Atp7b mice were <130% the weight of controls and <30% cancerous, and at 21 months the mice were still active. However thiamine was ineffective in a subcutaneous xenograft model. CONCLUSION This study suggests that thiamine may constitute a prophylactic for Wilson's disease-induced hepatocellular carcinoma.