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.
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.
Lock
E A
EA
Zeneca, Central Toxicology Laboratory, Alderley Park, Cheshire, UK.
Ellis
M K
MK
Gaskin
P
P
Robinson
M
M
Auton
T R
TR
Provan
W M
WM
Smith
L L
LL
Prisbylla
M P
MP
Mutter
L C
LC
Lee
D L
DL
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors*; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy; D000818:Animals; D003512:Cyclohexanones / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D006540:Herbicides / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D006801:Humans; D009579:Nitrobenzoates / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D014443:Tyrosine / Q000378:metabolism
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D006540:Herbicides; D009579:Nitrobenzoates; D014443:Tyrosine; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone