Rat strain differences in stereospecific 2-oxidation of RS-8359, a reversible and selective MAO-A inhibitor, by aldehyde oxidase.
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.
Department of Biopharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan.
Takamitsu
T
Sasaki
Akiko
A
Masubuchi
Mayumi
M
Yamamura
Nobuaki
N
Watanabe
Masahiro
M
Hiratsuka
Michinao
M
Mizugaki
Kunio
K
Itoh
Yorihisa
Y
Tanaka
D042931:Aldehyde Oxidase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D002384:Catalysis; D003600:Cytosol / Q000201:enzymology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000378:metabolism*; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; D012333:RNA, Messenger; C059590:RS 8359; D042931:Aldehyde Oxidase