The Origin of Central and Peripheral p-Hydroxyphenylacetic Acid in Man and Rats

Abstract

The effects of a number of monoamine oxidase, two types of dopadecarboxylase inhibitors and neomycin on the production of p-hydroxyphenylacetic acid (PHPA) and catecholamine metabolites were evaluated in an attempt to determine the origin of central and peripheral PHPA in rats. Acute intragastric (I.G.) administration of pargyline as well as chronic I.G. carbidopa, alpha-methyldopa (dopadecarboxylase inhibitors) and neomycin treatments failed to reduce PHPA concentration in the brain and urine, suggesting minor roles of gut flora and endogenously produced p-tyramine in the overall body production ot PHPA. Neomycin reduced p-Ty and increased PHPA excretion. Catecholamine metabolites, phenylethylamine and p-tyramine (p-Ty) excretions were altered according to the expected mode of action ot the drugs employed. Paradoxically, carbidopa (like alpha-methyldopa) significantly reduced hypothalamic norepinephrine and its metabolism, suggesting a central influence of carbidopa. Chronic administration of three types of monoamine oxidase (MAO) inhibitors, pargyline, clorgyline and deprenyl failed to reduced urine and brain PHPA. These drugs produced changes in phenylethylamine and catecholamine metabolite’s excretion and brain content that are consistent with effective inhibition of either or both MAO type A and B. By a process of elimination, it is concluded that while most body p-Ty is derived from p-tyrosine decarboxylation, most central and peripheral PHPA in rats and possibly man originate from p- tyrosine transamination to p-hydroxyphenylpyruvic acid followed by decarboxylation to PHPA. This conclusion was confirmed by demonstrating that the administration of p-hydroxyphenylpyruvic acid significantly elevated the excretion of PHPA as well as p-hydroxyphenyllactic acid and homogentisic acid. Blockade of p- tyrosine decarboxylation by carbidopa was also demonstrated to elevate the excretion of deuterated PHPA derived from administered deuterated p-tyrosine, thus adding support to the above conclusion. The contribution of p-tyramine metabolism towards total body output of PHPA is less than 30%. The role of the gut flora in the production of phenylethylamine and catecholamine metabolites was also concluded to be minor. A number of new observations related to p-Ty, PHPA and PEA were made. p-Ty was found to be almost completely excreted in rat in the conjugated form. In contrast most urine PHPA (around 80%) and PEA (70–90%) are excreted unconjugated. It is concluded that although p-Ty may be an important biogenic amine, its metabolism and turnover rate, unfortunately, cannot be assessed from the assay of PHPA.