Kidneys of mice with hereditary tyrosinemia type I are extremely sensitive to cytotoxicity.

摘要: Children with hereditary tyrosinemia type 1 (HT1) suffer from liver failure, renal tubular dysfunction, and rickets. The disease is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme tyrosine catabolism, leads to accumulation toxic substrate (FAA) in hepatocytes proximal cells. Patients are treated 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC), which prevents FAA blocking an upstream FAH. Liver transplantation performed when patients do not respond NTBC or develop hepatocellular carcinoma. This reduces load for kidney but does abolish exposure locally produced FAA. To investigate pathogenesis damage induced metabolites, we challenged FAH-deficient mice various doses homogentisic acid (HGA), a precursor Injecting NTBC-treated Fah−/−mice low HGA death cells, as was shown histologic analyses deoxynucleotidyl transferase-mediated dUDP nick-end labeling (TUNEL) assay did lead damage. In addition, function, affected after HGA. Administration high led massive cell both kidneys. Resistance HGA-induced seen withdrawing Fah−/−mice. finding that kidneys especially sensitive underscores need perform careful monitoring function undergoing any form treatment.