Reversible inhibition of aromatic hydroxylation of methamphetamine in rat liver microsomal preparations pretreated with methamphetamine.
The effects of a single and repeated administration of methamphetamine (MP) in vivo in rats on its own metabolism in vitro were investigated. In both cases, the p-hydroxylation of MP to p-hydroxymethamphetamine by a microsomal fraction from rat liver was inhibited for a period of 16 hr after the last injection of MP. This inhibition was diminished by dialysis of the microsomal preparations. In contrast, the reduced level of cytochrome P-450 in hepatic microsomes from rats pretreated with the SKF 525-A did not revert to the control value after dialysis. When microsomes were preincubated with N-hydroxymethamphetamine, which is the metabolite of MP and a potent substrate for the formation of a metabolic intermediate (MI) complex with cytochrome P-450, the content of the MI was increased and the MP-hydroxylation activity decreased in direct proportion to the length of the preincubation. These results suggest that the inhibition of MP-hydroxylation may be due to reduction of the level of cytochrome P-450 that accompanies the formation of the MI complex. Furthermore, it appears that the complex can be dissociated by dialysis.
Yamamoto
T
T
Department of Pharmacology, Medical College of Oita, Japan.
Takano
R
R
Egashira
T
T
Yamanaka
Y
Y
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003956:Dialysis; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D008694:Methamphetamine; C054335:N-hydroxymethamphetamine; D003577:Cytochrome P-450 Enzyme System