Nitisinone treatment protect hereditary tyrosinemia type I patients against inflammation, DNA and protein oxidative damage by decreasing succinylacetone levels

Metab Brain Dis. 2025 Sep 26;40(7):275. doi: 10.1007/s11011-025-01719-2.

Abstract

Hereditary tyrosinemia type I (HT1) is an inborn error of metabolism (IEM), caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), in the catabolic pathway of the semi-essential amino acid tyrosine (TYR), causing accumulation and formation of toxic metabolites such as succinylacetone (SA), which results in kidney and liver damage. Patients are treated with a low-protein diet and restriction of TYR and phenylalanine and administration of nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, which minimizes the formation of toxic metabolites. The literature has demonstrated the involvement of oxidative stress in the pathophysiology of tyrosinemia, but there is no informative data on patients under treatment. In this work, we evaluated oxidative stress and inflammation in patients with HT1 under treatment with NTBC, as well their SA levels in plasma and urine. We found a significant decrease in SA plasma and urine levels in treated patients compared to untreated patients and control group. We observed a decrease in IL-2 and an increase in IL-4, and non-significant differences were observed for the other cytokines, when compared to the control group. We did not observe significant differences between groups when evaluating total antioxidant status (TAS), oxidized guanine species, which represents oxidative damage to DNA/RNA, and sulfhydryl content, which represents oxidative damage to protein. When evaluating lipoperoxidation (TBARS) we found a significant increase for untreated patients in relation to the control group. Our study was the first to evaluate these parameters in HT1 patients treated with NTBC, and our results allow to suggest that the treatment appears to protect against inflammation, DNA and protein oxidative damage by decreasing SA levels.

Keywords: Hereditary tyrosinemia type I; Inflammation; Nitisinone; Oxidative stress; Succinylacetone.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Cyclohexanones* / pharmacology
  • Cyclohexanones* / therapeutic use
  • DNA Damage* / drug effects
  • Enzyme Inhibitors* / therapeutic use
  • Female
  • Heptanoates* / blood
  • Heptanoates* / metabolism
  • Heptanoates* / urine
  • Humans
  • Inflammation* / drug therapy
  • Inflammation* / metabolism
  • Inflammation* / prevention & control
  • Male
  • Nitrobenzoates* / pharmacology
  • Nitrobenzoates* / therapeutic use
  • Oxidative Stress* / drug effects
  • Tyrosinemias* / blood
  • Tyrosinemias* / drug therapy
  • Tyrosinemias* / metabolism

Substances

  • nitisinone
  • Cyclohexanones
  • Nitrobenzoates
  • succinylacetone
  • Heptanoates
  • Enzyme Inhibitors