Glycine conjugation of the substituted benzoic acids in vitro: structure-metabolism relationship study

The relationships between the chemical structure and glycine conjugation of 10 para- and 8 meta-monosubstituted, and 6 disubstituted benzoic acids were examined in the rat liver and kidney mitochondria. For the simultaneous determination of the acid and its glycine conjugate, a simple and specific high performance liquid chromatographic method was developed. The extent of glycine conjugation of a series of substituted benzoic acids in liver mitochondria was similar to that in kidney mitochondria. Glycine conjugation increased with greater lipid solubility. On the other hand, more bulky substituents at the p- or m-position on the benzene ring reduced the glycine conjugation. The dependence on van der Waals volume (Vw) values for substituents reflects the importance of steric effects in the glycine conjugation. However the steric effect of the substituent was slightly less pronounced at the m-position than at the p-position. These results indicate that an active site of the enzyme possess limited steric bulk tolerance.