The 4-O-methyl metabolites of catecholamines. Homo-iso-vanillin acid in rat urine and brain; urinary iso-vanyl compounds after intraperitoneal administration of dopamine and of dopamine precursors and derivatives

Abstract Homo- iso -vanillic acid (3-hydroxy, 4-methoxyphenylacetic acid, iso -HVA was detected in rat urine and brain, with a molar ratio of iso -HVA to HVA of 0·07 in urine and about 0·35 in brain. The free urinary iso -vanyl and vanyl phenolcarboxylic acids were studied after intraperitoneal loads with the following compounds: l -dopa, l -3-O- methyldopa , l -4-O- methyldopa , dopamine, 3-O-methyldopamine, 4- O -methyldopamine and 3,4-dihydroxyphenylacetic acid. The results suggest the following conclusions. (1) The molar ratio iso -HVA/HVA is not constant. After dopa as well as dopamine loads it rises with the increase of the dose of precursor administered, showing that, in vivo , the 4- O -methylation process depends, to some extent, on the substrate concentration. (2) In contrast with the other catechols (dopamine and 3,4-dihydroxyphenylacetic acid), l -dopa itself does not seem to be para - O -methylated. It is therefore unlikely that 4- O -methyldopa would be a metabolite of l -dopa in vivo . (3) Distinct urinary metabolites from l -3-O- methyldopa (vanylmandelic and vanillic acids) on one hand and from l -4-O-methyldopa (unknown iso -vanyl phenolcarboxylic acid) on the other, support evidence that some of the metabolic transformations of the side-chain of the O -methyl-catecholamines are different according to whether the methyl group is bound on the meta or on the para position. (4) The high level of cerebral iso -HVA might be due to either a lower iso -HVA than HVA transport outside the brain, or to the existence, in addition to the dopamine source, of a second cerebral metabolic pathway for the production of iso -HVA.