Selective involvement of cytochrome P450 2D subfamily in in vivo 4-hydroxylation of amphetamine in rat.
The cytochrome P450 (P450) 2D subfamily catalyzes ring hydroxylation of amphetamines. We tested the hypothesis that P450 2D is selectively involved in amphetamine 4-hydroxylation. Urinary elimination of 4-hydroxyamphetamine and amphetamine was determined in male Sprague-Dawley rats pretreated with P450 inducers and inhibitors. The urinary 24-h metabolic ratio (amphetamine/4-hydroxyamphetamine) was not affected by the inducers 3-methylcholanthrene, isosafrole, phenobarbital, ethanol, pregnenolone-alpha-carbonitrile, and clofibrate. Isosafrole did, however, increase amphetamine elimination along with urine volume. Urinary elimination of 4-hydroxyamphetamine was significantly decreased by, and the metabolic ratio increased by, the inhibitors 1-aminobenzotriazole, CCl(4), quinidine, quinine, and primaquine. Diallyl sulfide and troleandomycin had no effect. In rat liver microsomes primaquine was shown to be an inhibitor of 2D activity. Urine 4-hydroxyamphetamine content correlated strongly (r(2) = 0. 989) with microsomal P450 2D activity in parallel-treated rats. These studies also substantiate that 4-hydroxylation of amphetamine is selectively performed by the P450 2D subfamily in the rat.
Law
M Y
MY
Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112-9457, USA.
Slawson
M H
MH
Moody
D E
DE
D000661:Amphetamine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012451:Safrole / Q000494:pharmacology; D010136:p-Hydroxyamphetamine / Q000378:metabolism* / Q000652:urine
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011285:Pregnenolone Carbonitrile; D000431:Ethanol; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D000661:Amphetamine; D010136:p-Hydroxyamphetamine; D002994:Clofibrate; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital