Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase

Lindstedt, Sven

doi:10.1016/0140-6736(92)92685-9

Cited by 604 publications

(400 citation statements)

References 15 publications

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“…Sudden apoptotic death of unmasked phenotype of HT1 in mature and unmodified hepatocytes had not been expected (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)16), and these are implications for the pathogenesis and treatment of liver disease in HT1 patients. We suggest that mature and unmodified hepatocytes in those with the FAH defect cannot survive and that hepatocytes in the chronic form of HT1 have to be protected from a likely acute death.…”

Section: Discussionmentioning

confidence: 99%

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Endo¹,

Kubo²,

Awata³

et al. 1997

Journal of Biological Chemistry

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Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c 14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c 14CoS mice (c 14CoS /c 14CoS or Fah ؊/؊ ). The double mutant Fah ؊/؊ Hpd ؊/؊ mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah ؊/؊ on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah ؊/؊ undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah ؊/؊ Hpd ؊/؊ mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah ؊/؊ Hpd ؊/؊ mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.

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Section: Discussionmentioning

confidence: 99%

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Endo¹,

Kubo²,

Awata³

et al. 1997

Journal of Biological Chemistry

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“…This drug is registered in several countries for the treatment of hereditary tyrosinemia type I (HT-1, OMIM reference 276700) which is caused by a defect further downstream in the tyrosine metabolism pathway compared to AKU. In HT-1, nitisinone prevents the formation of the highly toxic metabolites maleylacetoacetate, fumarylacetoacetate, and succinylacetone (Lindstedt et al 1992), and in combination with a tyrosine-restricted diet, it serves as a successful therapeutic intervention. In AKU, nitisinone can effectively reduce HGA and prevent ochronosis in mice (Suzuki et al Preston et al 2013) and reduce HGA in patients (Introne et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

et al. 2015

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Background: Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported.Objectives: To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients.Method: Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment.Results: Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max ]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/hÁkg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 mmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations.Conclusion: Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

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“…Nitisinone at a dose of 1-2 mg/kg/day has been widely used for more than 20 years in the treatment of a lifethreatening condition called hereditary tyrosinaemia type 1 (HT-1) (Lindstedt et al 1992). Corneal involvement is not part of the natural history in HT-1.…”

Section: Introductionmentioning

confidence: 99%

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

et al. 2014

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We describe a patient with ultra-rare disease, alkaptonuria, who developed tyrosine keratopathy following nitisinone therapy of 2 mg on alternate days. His vision became impaired approximately 7 weeks following the commencement of nitisinone and ophthalmological examination at week nine showed characteristic dendritic keratopathy associated with tyrosinaemia. The corneal lesion as well as his visual symptoms normalized completely following discontinuation of nitisinone. This is the first documented report of keratopathy due to acquired tyrosinaemia due to very low-dose nitisinone.

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Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase

Cited by 604 publications

References 15 publications

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

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