Nitisinone is an orally active, competitive, and reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) with an IC50 of 173 nM. It increases tyrosine levels in a dose-dependent manner and is utilized in research related to hereditary tyrosinemia type 1 (HT-1), a rare genetic disorder, and albinism[1].[2].[3].[4].
体内研究
Administered orally at doses of 5 and 10 mg/kg, five days a week for six weeks, Nitisinone consistently inhibits 4-HPPD in rat liver in both a dose- and time-dependent manner[2].
Nitisinone, at a dose of 4 mg/kg administered orally once daily with a day's interval for a month, increases tyrosine levels in both OCA-1A and OCA-1B models[3].
The same dosing regimen of Nitisinone (4 mg/kg; orally; once daily; one day interval for one month) also enhances coat and iris pigmentation and increases melanin content in the melanosomes of ocular tissues in a mouse model of OCA-1B[3].
体外研究
Nitisinone (ranging from 0.01 to 10 μM over 72 hours) enhances tyrosine accumulation in a dose-responsive manner[1].
Nitisinone/尼替西农 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Saccharomyces cerevisiae
4 µg per gram of yeast
5.5 hours
Investigate the influence of nitisinone and its metabolites on yeast metabolism, finding that CHD caused a decrease in l-tyrosine, l-tryptophan, and l-phenylalanine concentrations by about 34%, 59% and 51%, respectively
Sci Rep. 2023 Jan 26;13(1):1473
Nitisinone/尼替西农 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Zebrafish
Slc24a5 knockout zebrafish model
Added to E3 medium
1.0, 2.5, 5, 10, 20, 50, 100, 150, and 200 μM
Drug water changed every 24 hours for 7 days
To evaluate the efficacy of nitisinone in improving melanin synthesis and pigmentation in the slc24a5 knockout zebrafish model, results showed no significant improvement in melanin content and pigmentation
Pigment Cell Melanoma Res. 2020 Jul;33(4):556-565
Mice
Tyrc-h/c-h mice (OCA-1B model) and Tyrc-2J/c-2J mice (OCA-1A model)
Oral gavage
4 mg/kg
Every other day for 1 month
To evaluate the effect of nitisinone on pigmentation in OCA-1B model mice. Results showed that nitisinone significantly increased fur and iris pigmentation in Tyrc-h/c-h mice but had no significant effect on Tyrc-2J/c-2J mice.
J Clin Invest. 2011 Oct;121(10):3914-23
BALB/c mice
HGD−/− mice (AKU model)
Drinking water
4 mg/L
Continuous for one week
To assess the effect of nitisinone-induced hypertyrosinaemia on monoamine neurotransmitters in a murine model of AKU. Results showed that nitisinone treatment significantly increased plasma tyrosine (9-fold) and decreased plasma homogentisic acid (9-fold), but no significant changes were observed in the distribution and intensity of dopamine, noradrenaline, and serotonin in brain tissue.
Metabolomics. 2019 Apr 29;15(5):68
BALB/c Hgd−/− mice
Murine Model of Alkaptonuria (AKU)
Drinking water
4 mg/L
Once daily for 6 days
To evaluate the impact of nitisinone on the CSF metabolome in a murine model of AKU, results showed significant increases in L-tyrosine and related metabolites post-treatment.
Metabolites. 2022 May 25;12(6):477
Mice
Alkaptonuria (AKU) mouse model
Oral administration via drinking water
4 mg/L (0.8 mg/kg)
Once daily for 7 days
To evaluate the effect of nitisinone on tyrosine metabolism pathway, results showed HGA was significantly decreased 8-fold and tyrosine increased 11-fold
J Inherit Metab Dis. 2020 Mar;43(2):259-268
Mice
OCA3 mouse model
Oral gavage
8 mg/kg
Every other day for 1 month
To evaluate the effect of Nitisinone on coat and ocular pigmentation in a mouse model of OCA3. Results showed that Nitisinone treatment significantly increased plasma tyrosine levels but did not improve coat or ocular pigmentation, with only a minimal increase in the number of pigmented melanosomes in the iris.
Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):4945-4952
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