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Am J Physiol Endocrinol Metab (March 16, 2004). doi:10.1152/ajpendo.00397.2003
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Submitted on September 2, 2003
Accepted on March 9, 2004

Role of renal D-amino-acid oxidase in pharmacokinetics of D-leucine

Hiroshi Hasegawa1*, Takehisa Matsukawa1, Yoshihiko Shinohara1, Ryuichi Konno2, and Takao Hashimoto1

1 Department of Pathophysiology, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan
2 Department of Microbiology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan

* To whom correspondence should be addressed. E-mail: hasegawa{at}ps.toyaku.ac.jp.

D-Amino acids are now recognized to be widely present in mammals. Renal D- amino-acid oxidase (DAO) is associated with conversion of D-amino acids to the corresponding {alpha}-keto acids, but its contribution in vivo is poorly understood because {alpha}- keto acids and/or L-amino acids formed are indistinguishable from endogenous compounds. First, we have examined whether DAO is indispensable for conversion of D-amino acids to their {alpha}-keto acids by using stable isotope tracer technique. After a bolus intravenous administration of D-[2H7]leucine to mutant mice lacking DAO activity (ddY/DAO-) and normal mice (ddY/DAO+), elimination of D-[2H7]leucine and formation of [2H7]{alpha}- ketoisocaproic acid ([2H7]KIC) and L-[2H7]leucine in plasma were determined. The ddY/DAO- mice, in contrast to ddY/DAO+ mice, failed to convert D-[2H7]leucine to [2H7]KIC and L-[2H7]leucine. This result clearly revealed that DAO was indispensable for the process of chiral inversion of D-leucine. We further investigated the effect of renal mass reduction by partial nephrectomy on elimination of D-[2H7]leucine and formation of [2H7]KIC and L-[2H7]leucine. Renal mass reduction slowed down the elimination of D-[2H7]leucine. The fraction of conversion of D-[2H7]leucine to [2H7]KIC in sham-operated rats was 0.77, whereas that in 5/6-nephrectomized rats was 0.25. The elimination behavior of D-[2H7]leucine observed in rats suggested that kidney was the principal organ responsible for converting D-leucine to KIC.




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[Abstract] [Full Text] [PDF]


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