Stereospecific oxidation of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, by aldehyde oxidase.
In a previous paper by the authors on RS-8359, a new selective and reversible monoamine oxidase A (MAO-A) inhibitor, it was reported that the (S)-enantiomer of RS-8359 is rapidly eliminated from rats, monkeys and humans as a result of the formation of a 2-oxidative metabolite. The present study investigates the properties of the enzyme responsible for the 2-oxidation of RS-8359. Subcellular localization, cofactor requirement and the inhibitory effects of typical compounds were studied using rat liver preparations. In addition, the enzyme was purified from rat liver cytosol for further characterization. The enzyme activity was localized in the cytosolic fraction without the need for any cofactor and was extensively inhibited by menadione, chlorpromazine and quinacrine. The purified enzyme was also a homodimer with a monomeric molecular weight of 140 kDa and it had an A280/A450 ratio of 5.1 in the absorption spectrum. The results suggest that the enzyme responsible for the biotransformation of RS-8359 to give the 2-keto derivative is aldehyde oxidase (EC 1.2.3.1). The reaction of aldehyde oxidase is highly stereoselective for the (S)-configuration of RS-8359 and the (9R)-configuration of cinchona alkaloids.
Itoh
K
K
Department of Biopharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan.
Yamamura
M
M
Muramatsu
S
S
Hoshino
K
K
Masubuchi
A
A
Sasaki
T
T
Tanaka
Y
Y
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D002930:Cinchona Alkaloids / Q000378:metabolism / Q000493:pharmacokinetics; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011803:Quinine / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014018:Tissue Distribution
D002930:Cinchona Alkaloids; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C041622:cinchonidine; C059590:RS 8359; D011803:Quinine; D042931:Aldehyde Oxidase; D008995:Monoamine Oxidase