RT Journal Article
SR Electronic
T1 Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 734
OP 739
DO 10.1124/dmd.106.011502
VO 35
IS 5
A1 Kunio Itoh
A1 Akiko Masubuchi
A1 Takamitsu Sasaki
A1 Mayuko Adachi
A1 Nobuaki Watanabe
A1 Kiyoshi Nagata
A1 Yasushi Yamazoe
A1 Masahiro Hiratsuka
A1 Michinao Mizugaki
A1 Yorihisa Tanaka
YR 2007
UL http://dmd.aspetjournals.org/content/35/5/734.abstract
AB One of major metabolic pathways of [(±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine] (RS-8359), a selective and reversible monoamine oxidase type A inhibitor, is the aldehyde oxidase-catalyzed 2-hydroxylation at the pyrimidine ring. Donryu rats showed a dimorphic pattern for the 2-oxidation activity with about 20- to 40-fold variations in the Vmax/Km values between a low and a high activity group. The rats were classified as extensive metabolizers (EM) and poor metabolizers (PM) of RS-8359, of which ratios were approximately 1:1. One rat among the EM rats of each sex showed extremely high activity, and they were referred to as ultrarapid metabolizers. There was no significant difference in the expression levels of mRNA of aldehyde oxidase between the EM and PM rats. Analysis of nucleotide sequences showed four substitutions, of which the substitutions at 377G>A and 2604C>T caused 110Gly-Ser and 852Ala-Val amino acid changes, respectively. Amino acid residue 110 is located very near the second Fe-S center of aldehyde oxidase. Its change from nonchiral Gly to chiral Ser may result in a conformational change of aldehyde oxidase protein with the shift of isoelectric point value from 5.0 in the EM rats to 6.2 in the PM rats. The 110Gly-Ser amino acid substitution (377G>A) may be primarily responsible for the variations of aldehyde oxidase activity observed in Donryu rats, in addition to the difference of expression levels of aldehyde oxidase protein. If a new drug candidate is primarily metabolized by aldehyde oxidase, attention should be given to using a rat strain with high aldehyde oxidase activity and small individual variation. The American Society for Pharmacology and Experimental Therapeutics