Molecular basis of the Dark Agouti rat drug oxidation polymorphism: importance of CYP2D1 and CYP2D2.
The Dark Agouti rat has been proposed as a model for the human debrisoquine 4-hydroxylase polymorphism. Earlier studies suggested that the poor metabolizer phenotype in the Dark Agouti rat is caused by the absence of the expression of CYP2D1 mRNA. Although CYP2D1 is the major enzyme catalyzing debrisoquine 4-hydroxylation, other reports have indicated the involvement of a CYP2D, purified from rat hepatic microsomes and presumed to be CYP2D2, which also exhibits this activity. The levels of CYP2D1 and CYP2D2 mRNAs were markedly lower in Dark Agouti as compared to Sprague Dawley rats. Using a baculovirus expression system, recombinant CYP2D1 and CYP2D2 from Spodoptera frugiperda insect cells were examined and were found to both forms catalize debrisoquine 4-hydroxylase activity. These results suggest that reduced debrisoquine 4-hydroxylase activity in the Dark Agouti rat is caused by the low level expression not only of CYP2D1, but also of CYP2D2. Interestingly, bunitrolol 4-hydroxylation was catalyzed by recombinant CYP2D2, while CYP2D1 was inactive toward this substrate. Thus, the low bunitrolol 4-hydroxylation in Dark Agouti rats was caused by the low level of CYP2D2 expression in this rat strain.
Yamamoto
Y
Y
Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Tasaki
T
T
Nakamura
A
A
Iwata
H
H
Kazusaka
A
A
Gonzalez
F J
FJ
Fujita
S
S
D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018411:Spodoptera
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; C084811:bunitrolol