Start Over

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

Authors :: Hiroshi Hasegawa
Takehisa Matsukawa
Yoshihiko Shinohara
Ryuichi Konno
Takao Hashimoto
Source :: American Journal of Physiology: Endocrinology & Metabolism; Jul2004, Vol. 287, pE160-E165, 6p, 7 Diagrams, 1 Chart
Publication Year :: 2004
Abstract: 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 α-keto acids, but its contribution in vivo is poorly understood because the α-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 α-keto acids by using the stable isotope tracer technique. After a bolus intravenous administration of d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine to mutant mice lacking DAO activity (ddY/DAO<superscript>−</superscript>) and normal mice (ddY/DAO<superscript>+</superscript>), elimination of d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine and formation of α-[<superscript>2</superscript>H<subscript>7</subscript>]ketoisocaproic acid ([<superscript>2</superscript>H<subscript>7</subscript>]KIC) and l-[<superscript>2</superscript>H<subscript>7</subscript>]leucine in plasma were determined. The ddY/DAO<superscript>−</superscript> mice, in contrast to ddY/DAO<superscript>+</superscript> mice, failed to convert d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine to [<superscript>2</superscript>H<subscript>7</subscript>]KIC and l-[<superscript>2</superscript>H<subscript>7</subscript>]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-[<superscript>2</superscript>H<subscript>7</subscript>]leucine and formation of [<superscript>2</superscript>H<subscript>7</subscript>]KIC and l-[<superscript>2</superscript>H<subscript>7</subscript>]leucine. Renal mass reduction slowed down the elimination of d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine. The fraction of conversion of d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine to [<superscript>2</superscript>H<subscript>7</subscript>]KIC in sham-operated rats was 0.77, whereas that in five-sixths-nephrectomized rats was 0.25. The elimination behavior of d-[<superscript>2</superscript>H<subscript>7</subscript>]leucine observed in rats suggested that kidney was the principal organ responsible for converting d-leucine to KIC. [ABSTRACT FROM AUTHOR]