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Am J Physiol Endocrinol Metab 287: E160-E165, 2004. First published March 16, 2004; doi:10.1152/ajpendo.00397.2003
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Role of renal D-amino-acid oxidase in pharmacokinetics of D-leucine

Hiroshi Hasegawa,1 Takehisa Matsukawa,1 Yoshihiko Shinohara,1 Ryuichi Konno,2 and Takao Hashimoto1

1Department of Pathophysiology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392; and 2Department of Microbiology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan

Submitted 2 September 2003 ; accepted in final form 9 March 2004

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 the {alpha}-keto acids and/or L-amino acids formed are indistinguishable from endogenous compounds. First, we examined whether DAO is indispensable for conversion of D-amino acids to their {alpha}-keto acids by using the 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 {alpha}-[2H7]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 five-sixths-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.

{alpha}-ketoisocaproic acid; kidney; nephrectomy


Address for reprint requests and other correspondence: H. Hasegawa, Dept. of Pathophysiology, School of Pharmacy, Tokyo Univ. of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan (E-mail: hasegawa{at}ps.toyaku.ac.jp).




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Renal D-Amino Acid Oxidase Mediates Chiral Inversion of NG-Nitro-D-arginine
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