TY - JOUR T1 - In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 250 LP - 256 DO - 10.1124/jpet.102.043174 VL - 305 IS - 1 AU - Chunze Li AU - Mark P. Grillo AU - Leslie Z. Benet Y1 - 2003/04/01 UR - http://jpet.aspetjournals.org/content/305/1/250.abstract N2 - Two alternative metabolic pathways, acyl glucuronidation and acyl-CoA formation, are implicated in the generation of reactive acylating metabolites of carboxylic acids. Here, we describe studies that determine the relative importance of these two pathways in the metabolic activation of a model substrate, 2-phenylpropionic acid (2-PPA), in vivo in rats. Male Sprague-Dawley rats were pretreated with and without (−)-borneol (320 mg/kg i.p.), an inhibitor of acyl glucuronidation, or trimethylacetic acid (TMA, 500 mg/kg i.p.), an inhibitor of acyl-CoA formation, before receiving 2-PPA (racemic, 130 mg/kg). After administration of 2-PPA, livers were collected over a 2-h period and analyzed for 2-PPA acyl glucuronidation and 2-PPA-CoA formation by high-performance liquid chromatography. Covalent binding was measured by scintillation counting of washed liver protein precipitates. Results showed that pretreatment with TMA led to a 49% decrease in covalent binding of 2-PPA to liver proteins, when a 64% decrease in the exposure of 2-PPA-CoA was observed. Conversely, 95% inhibition of acyl glucuronidation by (−)-borneol, led to a 23% decrease in covalent binding to protein. These results suggest that metabolic activation by 2-PPA-CoA formation contributes to covalent adduct formation to protein in vivo to a greater extent than metabolic activation by acyl glucuronidation for this model substrate. The American Society for Pharmacology and Experimental Therapeutics ER -