Role of renal D-amino-acid oxidase in pharmacokinetics of D-leucine.
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-[(2)H(7)]leucine to mutant mice lacking DAO activity (ddY/DAO(-)) and normal mice (ddY/DAO(+)), elimination of d-[(2)H(7)]leucine and formation of alpha-[(2)H(7)]ketoisocaproic acid ([(2)H(7)]KIC) and l-[(2)H(7)]leucine in plasma were determined. The ddY/DAO(-) mice, in contrast to ddY/DAO(+) mice, failed to convert d-[(2)H(7)]leucine to [(2)H(7)]KIC and l-[(2)H(7)]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-[(2)H(7)]leucine and formation of [(2)H(7)]KIC and l-[(2)H(7)]leucine. Renal mass reduction slowed down the elimination of d-[(2)H(7)]leucine. The fraction of conversion of d-[(2)H(7)]leucine to [(2)H(7)]KIC in sham-operated rats was 0.77, whereas that in five-sixths-nephrectomized rats was 0.25. The elimination behavior of d-[(2)H(7)]leucine observed in rats suggested that kidney was the principal organ responsible for converting d-leucine to KIC.
Hasegawa
Hiroshi
H
Dept. of Pathophysiology, School of Pharmacy, Tokyo Univ. of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. hasegawa@ps.toyaku.ac.jp
Matsukawa
Takehisa
T
Shinohara
Yoshihiko
Y
Konno
Ryuichi
R
Hashimoto
Takao
T
D000818:Animals; D003198:Computer Simulation; D003605:D-Amino-Acid Oxidase / Q000172:deficiency* / Q000378:metabolism; D007651:Keto Acids / Q000097:blood* / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000601:surgery; D007930:Leucine / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D007651:Keto Acids; C013082:alpha-ketoisocaproic acid; D003605:D-Amino-Acid Oxidase; D007930:Leucine