Isolation and identification of mercapturic acid metabolites of phenyl substituted acrylate esters from urine of female rats.

The urinary mercapturic acid excretion by female rats of methyl atropate (alpha-phenyl methyl acrylate) and methyl cinnamate (beta-phenyl methyl acrylate) has been studied. On the basis of the structures of these mercapturic acids the conclusion can be drawn that these compounds arise from a conjugation of glutathione with the acrylic esters in a Michael fashion. Previous administration of (tri-orthotolyl) phosphate (TOTP), a carboxy esterase inhibitor, enhances the capacity of the acrylate esters to alkylate glutathione in vivo. The amount increased from 1.5 to 22.8% of dose (1.0 mmol/kg) for methyl cinnamate and from 10.4 to 14.8% of dose (0.2 mmol/kg) for methyl atropate. Upon inhibition of the esterase activity the major actual mercapturic acid is a conjugate of the acrylate in which the ester function is retained. In the absence of an esterase inhibition the excreted mercapturic acid is a formal conjugate of the free acrylic acid (Fig. 1). No mercapturic acids could be detected which might arise from glutathione conjugation of a, beta-epoxyesters. Such epoxides are potential primary metabolites of unsaturated esters. They were not detected by in vitro experiments. Therefore, the intermediacy of glycidic esters in the biotransformation of these acrylic esters may be considered as highly unlikely.