Norepinephrine Metabolism in Man Using Deuterium Labelling: Origin of 4-Hydroxy-3-Methoxymandelic Acid

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Abstract
A double isotope labeling technique was used to simultaneously determine the in vivo turnover rates of 4-hydroxy-3-methoxyphenylglycol (HMPG) and 4-hydroxy-3-methoxymandelic acid (HMMA, VMA) and the rate of HMPG oxidation to HMMA. Six healthy men were given i.v. injections of [2H3]HMPG and [2H6]HMMA and their plasma and urine samples analyzed by gas chromatography-mass spectrometry (GC/MS) for the protium and deuterium species. HMPG and HMMA production rates were calculated by isotope dilution. The rate of HMPG oxidation to HMMA was obtained from the fraction of [2H3]HMPG recovered as [2H3]HMMA. The entire production of HMMA, 1.11 .+-. 0.21 .mu.mol/h (mean .+-. SE), could be accounted for by oxidation of HMPG, 1.49 .+-. 0.31 .mu.mol/h. A tracer dose of [14C]HMPG was given to the same subjects. The levels of [14C]HMPG and [14C]HMMA were measured in urine after extraction and separation by TLC. Urinary excretion of endogenous HMPG and HMMA was determined by GC/MS. The endogenous HMMA fraction of the total HMPG and HMMA urinary excretion rate, 0.57 .+-. 0.04, was the same as the fraction of [14C]HMPG is oxidized to [14C]HMMA, 0.62 .+-. 0.01. HMPG is the main intermediate in the metabolic conversion of norepinephrine to epinephrine to HMMA in man.