Hereditary tyrosinemia type

Leptospermone (34) Nitisinone (35) P Triketone Hereditary tyrosinemia type 1... 

Leptospermone (34), a representative of an important new class of herbicides from the bottlebrush plant, Callistemon citrinus (Curtis) Skeels, has been found to have an inhibitory effect on the enzyme, -hydroxyphenylpyruvate dioxygenase (HPPD), involved in the synthesis of plastoquinone in plants. Nitisinone (35), a synthetic derivative of (34), has recently been introduced to the market for the treatment of hereditary tyrosinemia type 1 (HT-1), a severe genetic disease caused by a deficiency of fumaryl acetoacetate hydrolase (FAH). ... 

Nitisinone is a reversibile inhibitor of 4-hydroxy-phenylpyruvate oxidase, an enzyme that plays a crucial role in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic metabolites fumaryl acetoacetate, succinyl acetoacetate and succinyl acetone. Nitisinone is used for the treatment of hereditary tyrosinemia type 1. After oral administration bioavailability is 90% and peak levels are reached at 2.5 hours after dosing. The drug is eliminated mainly in the urine but some CYP3A4-mediated metabolism seems to occur. The elimination half-life is 45 hours. Blood dyscrasias are frequently occurring side effects as are eye problems like conjunctivitis, corneal opacity and keratitis. Exfoliative dermatitis, erythematous rash and pruritus... 

Nitisinone is an inhibitor of 4-hydroxyphenyIpyruvate dehydrogenase (4-HPPD). Originally studied as a herbicide, it is now marketed to prevent hepatic damage caused by hereditary tyrosinemia type I. This genetic disease is due to the absence in the body of fumarylacetoacetase, which ensures the last step of tyrosine degradation (Figure 8.86). 

D.L. Hereditary tyrosinemia type I (chronic form) Pathologic findings in the liver. Hum. Path. 1989 20 149-158... 

Jakobs C, Dorland L, Wikkerink B, Kok RM, de Jong AP, Wadman SK. Stable isotope dilution analysis of succinyiacetone using electron capture negative ion mass fragmentography an accurate approach to the pre- and neonatal diagnosis of hereditary tyrosinemia type I. CHn Chim Acta 1988 171 223-31. 

Cytosolic tyrosine aminotransferase (EC 2.6.1A). Elevated tyrosine in blood and cerebrospinal fluid. Increased urinary tyrosine, 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenyiaeetate. Slight to moderate mental retar tion. Blistering and hyperkeratosis of palms and soles of feet. Photophobia. No hepatorenal dysfunction (cf. Hereditary tyrosinemia type I). Controlled with diet low in phenylalanine and tyrosine. 

Hereditary tyrosinemia type I, or Tyrosinosis, or Hereditary hepatorenal dysfunction (see Fig. 2). 

Succinylacatoacetata see Inborn errors of metabolism (hereditary tyrosinemia type I). 

Schulze A, Frommhold D, Mayatepek E, Hoffmann GF (2000) A new approach in neonatal screening for hereditary tyrosinemia type 1. J Inher Metab Dis 23, Suppl 1 7... 

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