Effects of sulcotrione [2-(2-chloro-4-mesylbenzoyl)-cyclohexane-1,3-dione] on enzymes involved in tyrosine catabolism and the extent of the resulting tyrosinemia and its relationship with corneal lesions in rats

We aimed to investigate the effects of subchronic exposure to sulcotrione on the enzymes involved in tyrosine catabolism and the extent of the resulting tyrosinemia and corneal lesions in rats. Daily oral administration of sulcotrione at 0.1, 0.5, 5, 50 and 100 mg/kg/day markedly inhibited hepatic 4-hydroxy-phenylpyruvate dioxygenase (HPPD). In response to the tyrosinemia, the activity of hepatic tyrosine aminotransferase (TAT) at each dose level was insignificantly induced and hepatic homogentisic acid oxidase (HGO) at 5, 50 and 100 mg/kg/day was markedly reduced. Repeated oral administration of sulcotrione to rats at doses of 5, 50, and 100 mg/kg/day for 90 days produced corneal lesions with an incidence of 18.8%, 75.0% and 56.3%, respectively. The significant increase in tyrosine levels indicates that the occurrence of corneal lesions in rats exposed to sulcotrione was not only associated with the concentration of tyrosine in the ocular fluid, but also with other, unidentified factors. (C) 2010 Elsevier Inc. All rights reserved.