A New Assessment of In Vivo Enzyme Activities in Metbolic Disorders Using Stable Isotope Methodology

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The pharmacokinetics of _L-histidine in human has been investigated to evaluate the in vivo histidine ammonia-lyase system for the conversion of _L-histidine to urocanic acid. Two healthy volunteers (subjects A and B) received a single 100-mg oral dose of _L-[3,3-^2H_2,1', 3'-^<15>N_2] histidine. Blood and urine samples were obtained over 24 hr after the administration and analyzed by stable isotope dilution mass spectrometry. The pharmacokinetic parameters were calculated based on a two-compartment model. The labeled _L-histidine in subject A (t_<1/2>=1.0hr) was eliminated approximately twice faster than that in subject B (t_<1/2>=1.9hr). The total body clearances (CL_T) were 70.0 liters/hr in subject A and 30.0 liters/hr in subject B.The low ratios of the renal clearance to the total body clearance (CL_<re>/CL_T ; 1.04% for subject A and 0.43% for subject B) indicated that most of _L-histidine was eliminated via the non-renal processes._L-Histidine was rapidly metabolized to urocanic acid. The maximum plasma concentrations of urocanic acid were 59.61 ng/ml at 30 min for subject A and 46.10 ng/ml at 60 min for subjectB.The slope of the plot of urinary excretion rate of urocanic acid vs.the plasma concentration of unchanged _L-histidine was demonstrated to reflect the metabolic clearance of _L-histidine to urocanic acid. The method of evaluating the in vivo human histidine ammonialyase activities discussed in this study offers a significant value with regard to the biochemical and clinical elucidations of the heterogeneity of histidinemia.