From toxicological problem to therapeutic use: The discovery of the mode of action of 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione (NTBC), its toxicology and development as a drug

Abstract

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations 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 dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.

Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs

“…This pharmacologic intervention prevents the formation of maleyl- and fumarylacetoacetate as well as relevant derivatives all of which are known to cause the pathologies observed in TYR I [8]. Along with a phenylalanine and tyrosine reduced diet, oral NTBC has become the mainstay of treatment for TYR I patients.…”

Inhibition of para‐Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria

“…[8][9][10][11] Because pre-clinical toxicological and pharmacokinetic data for 1 are mainly derived from comprehensive records based on different animal models, [12][13][14] human safety margins cannoty et be fully determined. [8][9][10][11] Because pre-clinical toxicological and pharmacokinetic data for 1 are mainly derived from comprehensive records based on different animal models, [12][13][14] human safety margins cannoty et be fully determined.…”

The Discovery of Medicines for Rare Diseases

“…In patients with hereditary tyrosinemia type 1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Nitisinone was originally discovered as an herbicide, but early mechanism-of-action studies in rats revealed that the compound caused a marked increase in plasma tyrosine concentrations [22]. …”