title: A review of the mode of toxicity and relevance to humans of the triketone herbicide 2-(4-methylsulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione.
abstract: The mode of action (MoA) of the herbicide mesotrione has been empirically established in experimental animals. In this review, we evaluate this MoA and the relevance of this MoA to humans against accepted scientific criteria. The key events in the MoA involve inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), the second enzyme in the tyrosine catabolic pathway, resulting in excess plasma tyrosine (tyrosinemia). When HPPD is completely inhibited, the clearance of excess tyrosine is dependent upon catabolism by the first and rate-limiting enzyme in the catabolic pathway, tyrosine aminotransferase (TAT) and elimination of the products of this catabolism via the urine. The inherent activity of TAT is low in rats and hence they catabolize tyrosine slowly and accumulate tyrosine to very high concentrations in plasma which results in a spectrum of adverse effects that are related to excess tyrosine. There is a large database showing a positive correlation between a range of biological endpoints and elevations in plasma tyrosine. Evidence is presented that clearly establishes a MoA involving tyrosine. Although plausible in humans, the extent and duration of plasma tyrosine elevation in humans is not sufficient to cause adverse effects resulting from the intended use of this herbicide.
authors: Syngenta Product Safety, Jealott's Hill International Research Centre, Bracknell, Berkshire, UK. dick.lewis@syngenta.com
authors: Richard W
authors: RW
authors: Lewis
authors: Jane W
authors: JW
authors: Botham
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors; D000818:Animals; D003512:Cyclohexanones / Q000494:pharmacology* / Q000506:poisoning / Q000633:toxicity; D006540:Herbicides / Q000494:pharmacology* / Q000506:poisoning / Q000633:toxicity; D006801:Humans
chemical_list: D003512:Cyclohexanones; D006540:Herbicides; D015111:4-Hydroxyphenylpyruvate Dioxygenase