Long‐term therapy with NTBC and tyrosine‐restricted diet in a murine model of hereditary tyrosinemia type I
Abstract
In human patients with hereditary tyrosinemia type I (HT1) a combination therapy of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexane dione (NTBC) and dietary restriction of phenylalanine and tyrosine is currently widely used. We previously reported that the use of NTBC in a murine model of HT1 abolished acute liver failure but did not prevent the development of hepatocellular carcinoma (HCC) in the setting of nonrestricted protein intake. Here we present the results obtained with higher doses of NTBC plus dietary tyrosine restriction on long-term follow up (>2 years). Liver function tests and succinylacetone levels were completely corrected with this regimen and cancer-free survival was improved when compared to historical controls. However, while no HT1 animals had HCC at age 13 months, the incidence was 2/16 (13%) at age 18 months and 1/6 (17%) after 24 months. Thus, even the most stringent therapy could not prevent the emergence of HCC in the mouse model of HT1, even when initiated prenatally.
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Toxic metabolite accumulation can be blocked by NTBC administration, a pharmacological inhibitor that blocks the pathway upstream of FAH.
“Toxic metabolite accumulation can be blocked by 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) administration, a pharmacological inhibitor that blocks the pathway upstream of FAH.23”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [23]
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- Authors
- Al-Dhalimy, M., Overturf, K., Finegold, M., & Grompe, M.
- Affiliations
- Oregon Health & Science University (US)
- Texas Children's Hospital (US)
- Corresponding author
- Grompe, M.
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 75
- Issue
- 1
- Pages
- 38-45
- ISSN
- 1096-7192 (ISSN-L)
- OpenAlex
- W1971901001
- Semantic Scholar
- 0f806f1d7d45dea253cfc3ee090b2540f1bad3d6
- Cited by
- 86
- References
- 27
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, R01-DK48252)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- tyrosinemia type I, NTBC, phenylalanine restriction, hepatocellular carcinoma, succinylacetone, long-term treatment, mouse model, fetal therapy, liver failure, tumor-free survival
- MeSH terms
- Animals, Cyclohexanones, Diet, Disease Models, Animal, Enzyme Inhibitors, Hydrolases, Nitrobenzoates, Phenylalanine, Tyrosine, Mice, Knockout, Tyrosinemias, Mice
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