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Pipecolic acid, a metabolite of lysine, is found in human physiological fluids. It is known that plasma pipecolic acid levels are elevated in patients with Zellweger syndrome, a genetic disorder, and chronic liver diseases. However, it is uncertain if this acid originates directly from food intake or from mammalian or intestinal bacterial enzyme metabolism. To characterize the relationship between plasma pipecolic acid and diet, we analyzed the contents of pipecolic acid in 17 edible plants and changes in plasma and urinary pipecolic acid levels following soybean juice ingestion by 4 healthy volunteers. Our study revealed that some of the plants contained high concentrations of total pipecolic acid, and a higher portion of L-isomer than D-isomer. Loading tests demonstrated that plasma levels and urinary excretion of D-isomer increased significantly 2 h after soybean juice ingestion. Plasma lysine levels showed a similar increase to that of D-isomer. These findings suggest that plasma pipecolic acid, particularly the D-isomer, originates mainly from the catabolism of dietary lysine by intestinal bacteria rather than by direct food intake and that D- and L-isomer may have different mechanisms of metabolism. Moreover, these findings may be important for clarifying the pathogenesis of peroxisomal disorders.

A sensitive and accurate stable isotope dilution assay was developed for the measurement of pipecolic acid in body fluids using electron capture negative ion mass fragmentography. The method utilizes [2H11]pipecolic acid as the internal standard. Sample preparation consisted of derivatization in aqueous solution (pH 11.5) of the amine moiety with methyl chloroformate to the N-methylcarbamate, followed by acidic ethyl acetate extraction (pH 2) and further derivatization of the carboxyl moiety to the pentafluorobenzyl ester. Normal values have been determined in cerebrospinal fluid (mean means = 0.041 mumol/l, range 0.010-0.120 mumol/l), in plasma of at term infants (age less than 1 wk, means = 5.73 mumol/l, range 3.75-10.8 mumol/l; age greater than 1 wk, means = 1.46 mumol/l, range 0.70-2.46 mumol/l), in urine of at term infants (age less than 6 mth, means = 32.5 mumol/g. creat., range 9.81-84.5 mumol/g. creat; age greater than 6 mth, means = 6.35 mumol/g. creat., range 0.15-13.6 mumol/g. creat.) and in amniotic fluid (means = 4.65 mumol/l, range 2.24-8.40 mumol/l). The utility of the method was demonstrated for the pipecolic acid quantification in these biofluids of patients with peroxisomal disorders. As affected fetuses with infantile Refsum's disease and Zellweger syndrome showed no significant elevation of pipecolic acid in their surrounding amniotic fluids, the measurement of pipecolic acid in amniotic fluid seemed not to be useful for prenatal diagnosis in these disorders.

A method is described for the quantitative assay of pipecolic acid in biological fluids using column chromatography, with acid ninhydrin for color development. The technique permits measurement of plasma pipecolic acid in normal individuals with blood samples of 1 ml. The mean value in 29 pediatric patients, aged 4 months to 17 years, hospitalized with a variety of diagnoses was 2.1 mumol/1 +/- 1.6. Newborn infants had slightly elevated plasma levels with a mean of 12 mumol/1 +/- 5.6. Among the diagnostic categories, patients with liver disease were distinctive in commonly having levels at the upper limits of normal. In some cases, the levels were exceedingly high, reaching 78 mumol/1 in one fatal case.