Major role of the CYP2C isozymes in deamination of amphetamine and benzphetamine: evidence for the quinidine-specific inhibition of the reactions catalysed by rabbit enzyme.
1. The cytochrome P450 isozymes involved in the deamination of amphetamine (AP) and benzphetamine (BZP) have been studied in liver microsomes from rabbit and rat using isozyme-specific inhibitors. 2. Metabolism of BZP in rat yielding phenylacetone and formaldehyde was moderately inhibited by testosterone and chloramphenicol. N-Debenzylation was thought to be P450-dependent, but all inhibitors except for a non-specific inhibitor, SKF-525A, failed to inhibit this reaction. 3. In rabbit, quinidine and testosterone were potent inhibitors of both BZP deamination and dealkylation. Deamination of AP in rabbit was extensively inhibited only with quinidine. 4. AP deamination with purified rabbit CYP2C3, which was previously identified as the major isozyme responsible for this metabolism, was extensively inhibited with quinidine, previously thought to be a specific inhibitor of CYP2D. 5. These results strongly support the notion that the CYP2C isozymes play a major role in the deamination of both AP and BZP, but not for N-debenzylation of BZP in rat. However, on the basis of different sensitivities toward inhibitors, multiple isozymes seem to be involved in BZP deaminations in both species.
Shiiyama
S
S
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Soejima-Ohkuma
T
T
Honda
S
S
Kumagai
Y
Y
Cho
A K
AK
Yamada
H
H
Oguri
K
K
Yoshimura
H
H
D000661:Amphetamine / Q000493:pharmacokinetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001589:Benzphetamine / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D003641:Deamination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity
D000697:Central Nervous System Stimulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D001589:Benzphetamine; D003577:Cytochrome P-450 Enzyme System; D000661:Amphetamine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D011802:Quinidine