FROM TOXICOLOGICAL PROBLEM TO THERAPEUTIC USE - THE DISCOVERY OF THE MODE OF ACTION OF TRO-4-TRIFLUOROMETHYLBENZOYL)-1,3-CYCLOHEXANEDIONE (NTBC), ITS TOXICOLOGY AND DEVELOPMENT AS A DRUG

NTBC is a triketone with herbicidal activity that has been shown to ha ve a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyru vate dioxygenase in plants. Early studies on the toxicity of this comp ound found that rats treated with NTBC developed corneal lesions. inve stigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate diox ygenase. The corneal lesions resemble those seen when rats are fed a d iet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained ty rosinaemia. Studies in collaboration with Professor Sven Lindstedt sho wed that NTBC was a potent inhibitor of purified human liver 4-hydroxy phenylpyruvate dioxygenase. This interaction lead to the concept of us ing NTBC to treat patients with tyrosinaemia type 1, to block or reduc e the formation of toxic metabolites such as succinylacetoacetate in t he liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC: a vailable for clinical use and, with the approval of the Swedish Medica l Products Agency, a seriously ill child with an acute form of tyrosin aemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and othe r countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.