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 V max/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.
ASJC Scopus subject areas
- Pharmaceutical Science