Metabolism of Arylacetic Acids: 4. Physico-Chemical, Structural and Biological Factors Influencing the Pattern of Conjugation

Abstract

1. Lipid solubility, the Hansch log P value, degree of ionization, affinities for specific binding to subcellular structures and extent of metabolic conjugation with glycine or glucuronic acid in vitro have been investigated for phenylacetic acid, 1-naphthylacetic acid, hydratropic acid and diphenylacetic acid.

2. Isolated rat liver mitochondria have a specific saturable binding site for arylacetic acids, the affinity for binding being in the order: phenylacetic acid >>> 1-naphthylacetic acid >> diphenylacetic acid > hydratropic acid.

3. Isolated rat liver mitochondria conjugate arylacetic acids with glycine, the relative affinities (% substrate converted to glycine conjugate) being phenylacetic acid (89), 1-naphthylacetic acid (1), diphenylacetic acid (0) and hydratropic acid (0).

4. 1-Naphthylacetic acid, hydratropic acid and diphenylacetic acid show extensive non-specific entrapment by isolated rat liver microsomes. There is also a saturable specific interaction, but with little difference between the four arylacetic acids in this respect.

5. Isolated rat liver microsomes conjugate arylacetic acids with glucuronic acid, the relative affinities (% substrate converted to the glucuronic acid conjugate) being diphenylacetic acid (28), 1-naphthylacetic acid (15), hydratropic acid (14) and phenylacetic acid. (0)

6. It is concluded that the main factor influencing glycine conjugation of an arylacetic acid is chemical structure. In particular, α-substitution of the methylene group of phenylacetic acid leads to loss of affinity for specific interaction with the mitochondrial binding site and to failure to undergo glycine conjugation in vitro and in vivo. By contrast glucuronic acid conjugation of arylacetic acids seems to be favoured by extensive non-specific entrapment by the endoplasmic reticulum, a process related more to lipid solubility than to chemical structure.