Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in a model of rat designated a poor metabolizer of debrisoquine.
The relationship between oxidative polymorphisms and the cause of Parkinson's disease is controversial. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces parkinsonism in humans and in some animal models, is metabolized by cytochrome P450 db1 isozyme (the same enzymatic system implicated in 4-hydroxylation of debrisoquine). In this study, we treated females of three rat species, which differ in their ability to hydroxylate debrisoquine, with MPTP (three doses of 30 mg/kg s.c. at 12-h intervals), and we measured their motor activity and brain monoamine levels. Female dark-adapted rats (poor metabolizers of debrisoquine) showed a more pronounced and more maintained reduction of their motor activity after treatment with MPTP. MPTP-treated, dark-adapted rats also had a depletion of noradrenaline in the diencephalon and a depletion of dopamine and serotonine and their respective metabolites in the limbic system when compared with the other two species. These results suggest that oxidative polymorphism of debrisoquine plays a role in the acute effects of MPTP.
Jiménez-Jiménez
F J
FJ
Service of Neurology, Hospital Universitario San Carlos, Spain.
Tabernero
C
C
Mena
M A
MA
García de Yébenes
J
J
García de Yébenes
M J
MJ
Casarejos
M J
MJ
Pardo
B
B
García-Agundez
J A
JA
Benítez
J
J
Martínez
A
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003623:Dark Adaptation; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003647:Debrisoquin; D009638:Norepinephrine