Rat strain differences in stereospecific 2-oxidation of RS-8359, a reversible and selective MAO-A inhibitor, by aldehyde oxidase

• Published in: Biopharmaceutics & drug disposition Vol. 27; no. 5; pp. 247 - 255
• Main Authors: Sasaki, Takamitsu, Masubuchi, Akiko, Yamamura, Mayumi, Watanabe, Nobuaki, Hiratsuka, Masahiro, Mizugaki, Michinao, Itoh, Kunio, Tanaka, Yorihisa
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.07.2006; Wiley
• Subjects: aldehyde oxidase; Aldehyde Oxidase - analysis; Aldehyde Oxidase - genetics; Aldehyde Oxidase - metabolism; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Blotting, Northern; Catalysis; Cytosol - enzymology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Liver - enzymology; Male; MAO-A inhibitor; Mice; Monoamine Oxidase Inhibitors - metabolism; Nitriles - metabolism; Oxidation-Reduction; Oxidoreductases; Pyrimidines - metabolism; rat; Rats; Rats, Inbred Strains; RNA, Messenger - analysis; RNA, Messenger - metabolism; RS-8359; Stereoisomerism; stereoselectivity; strain differences; Rat; Enzyme; Rodentia; Strain specificity; Metabolism; MAO-A inhibitor; Isomer; Monoamine oxidase A inhibitor; strain differences; Stereoselectivity; Vertebrata; Mammalia; Animal; Aldehyde oxidase; Oxidation; Oxidoreductases; Pharmacokinetics; RS-8359
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.504

Aldehyde oxidase catalysed 2‐oxidation activity of the (S)‐enantiomer of RS‐8359, a selective and reversible monoamine oxidase A (MAO‐A) inhibitor, was investigated in liver cytosolic fractions from ten rat strains. Remarkably large strain differences were observed with approximately a 230 variation between the highest activity in the Wistar‐Imamichi strain and the lowest activity in the Slc:Wistar strain. The activities of Crj:SD and Slc:SD strain rats were considerably low, and that of the F344/DuCrj strain was very low. Among six Wistar strains, Crj:Wistar, Slc:Wistar, WKY/Izm, WKAH/Hkm, Jcl:Wistar and Wistar‐Imamichi, the Slc:Wistar strain rats showed exceptionally low 2‐oxidation activity that was comparable to that of the F344/DuCrj strain. The rat strain differences in the catalytic activity of aldehyde oxidase could correlate in part with the expressed levels of protein based on the mRNA of aldehyde oxidase. However, no small discrepancy existed in the almost negligible catalytic activity and the fairly high expression levels of protein and mRNA in the F344/DuCrj and Slc:Wistar strain rats. Some genetic factors might possibly be one of reasons for the discrepancy. Copyright © 2006 John Wiley & Sons, Ltd.