Abstract— Employing both the intraventricular and intraperitoneal injection techniques, 14C‐l‐lysine at non‐overloading concentrations was found to be metabolized to l‐14C‐pipecolic acid at significantly high levels in the rat. Labeled pipecolic acid in the brain and liver was only found at rather low levels 24 h after intraperitoneal administration of 14C‐l‐lysine regardless of non‐labeled lysine metabolite overload. A marked enhancement of pipecolic acid labeling was only found in the brain when 14C‐l‐lysine was intraventricularly administered to animals under various lysine metabolite overloads. While overloading doses of non‐labeled saccharopine or α‐aminoadipate did not significantly alter the labeling patterns of pipecolic acid in the brain, liver or urine when 14C‐l‐lysine was intraperitoneally administered, pipecolate overloading markedly reduced labeled pipecolic acid levels in the brain, liver and urine. These results indicate: pipecolic acid formation is subject to product inhibition, and saccharopine is not in the pathway of pipecolic acid synthesis from l‐lysine. The labeling pattern of lysine metabolites was not significantly affected by the overloading injection of pipecolic acid when 14C‐l‐lysine was intraventricularly administered suggesting a blood‐brain barrier for pipecolate. Besides 14C‐pipecolic acid, labeled α‐aminoadipic acid was also found at significant levels mostly in the brain. Labeled saccharopine was not detected in any tissues or urine samples analyzed. The 14C‐l‐lysine metabolic pattern of the newborn rats did not seem to be any different from the adult rats, i.e. labeled pipecolic acid was also detected in substantial quantities in the brain, liver and urine 5 h after injection. 14C‐d‐Lysine was mainly metabolized to l‐14C‐pipecolic acid through either route of administration. These experimental evidences indicate that the pipecolic acid‐forming pathway is a significant route for lysine metabolism in the rat, and that the rat brain probably utilizes this pathway mainly for lysine metabolism. The present study also discusses the potential neurological significance of the pipecolic acid pathway in relation to the major lysine metabolic pathway (the saccharopine pathway).

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Metabolism of L-[U-14C]lysine was studied in the human autopsy tissues and the intact monkeys through intracerebroventricular and intravenous injections. The human tissues were more active in the metabolism of L-[14C]lysine to [14C]pipecolate than the rat tissues previously reported. This metabolism was equally active in the phosphate (pH 7) and the glycyl-glycine (pH 8.6) buffers with the brain and the kidney having higher activity than the liver. Besides [14C]pipecolate, traces of [14C]saccharopine and alpha-[14C]aminoadipate were also detected in the liver incubation. Twenty-four hr after intraventricular injection of L-[14C]lysine to the monkey, substantial labeling of pipecolate and alpha-aminoadipate was observed in the brain and spinal cord, with the kidney, liver and the plasma having much reduced levels. Radioactivity levels of these two compounds were found low in the organs and plasma of the intravenously injected monkey. The urine of both monkeys contained only traces of [14C]pipecolate, even though it contained high levels of L-[14C]lysine and alpha-[14C]aminoadipate. It was concluded that L-lysine is actively metabolized to pipecolate and alpha-aminoadipate in the human and the monkey, that this reaction is most active in the brain when L-lysine is intraventricularly administered, and that in contrast to the rat, the monkey may have an effective renal reabsorption for pipecolate which is similar to the human.

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