Nitisinone

Nitisinone is an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), which converts 4-hydroxyphenylpyruvate (HPPA) to homogentisate in the tyrosine catabolic pathway.¹ Nitisinone increases urinary levels of HPPA and 4-hydroxyphenyllactate (HPLA) in rats when administered at a dose of 10 mg/kg. Nitisinone (3 mg/kg) prevents the neonatal lethality of fumarylacetoacetate hydrolase (FAH) deficiency in mice when administered to pregnant dams.² It exhibits hepatoprotective effects in FAH^-/- mice, such as prevention of increases in plasma levels of aspartate serine aminotransferase (AST) and conjugated bilirubin, when administration is continued following birth at a dose of 1 mg/kg. Nitisinone (100 μg) decreases urinary excretion of homogentisate and increases urinary excretion of HPPA, HPLA, and 4-hydroxyphenylacetate in a mouse model of alkaptonuria induced by ethylnitrosourea.³ Formulations containing nitisinone have been used in the treatment of hereditary tyrosinemia type 1 (HT-1).

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1. Ellis, M.K., Whitfield, A.C., Gowans, L.A., et al. Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol. Appl. Pharmacol. 133(1), 12-19 (1995).

2. Grompe, M., Lindstedt, S., al-Dhalimy, M., et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat. Genet. 10(4), 453-460 (1995).

3. Suzuki, Y., Oda, K., Yoshikawa, Y., et al. A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J. Hum. Genet. 44(2), 79-84 (1999).