Reductive metabolism of an alpha,beta-ketoalkyne, 4-phenyl-3-butyn-2-one, by rat liver preparations.
The reduction of the triple bond and carbonyl group of an alpha,beta-ketoalkyne, 4-phenyl-3-butyn-2-one (PBYO), by rat liver microsomes and cytosol was investigated. The triple-bond-reduced product trans-4-phenyl-3-buten-2-one (PBO) and the carbonyl-reduced product 4-phenyl-3-butyn-2-ol (PBYOL) were formed when PBYO was incubated with rat liver microsomes in the presence of NADPH. The triple bond of 1-phenyl-1-butyne, deprenyl, ethynylestradiol, ethinamate, and PBYOL, in which the triple bond is not adjacent to a carbonyl group, were not reduced by liver microsomes even in the presence of NADPH. PBO was further reduced to 4-phenyl-2-butanone (PBA) by liver cytosol with NADPH. PBYOL was also formed from PBYO by liver cytosol in the presence of NADPH or NADH. The microsomal triple-bond reductase activity was inhibited by disulfiram, 7-dehydrocholesterol, and 18 beta-glycyrrhetinic acid but not beta-diethylaminoethyldiphenylpropylacetate or carbon monoxide. The triple-bond reductase activity in liver microsomes was not enhanced by several inducers of the rat cytochrome P450 system. These results suggested that the triple-bond reduction is caused by a new type of reductase, not cytochrome P450. The microsomal and cytosolic carbonyl reductase activities were not inhibited by quercitrin, indomethacin, or phenobarbital. Only S-PBYOL was formed from PBYO by liver cytosol. In contrast, liver microsomes produced R-PBYOL together with the S-enantiomer to some extent. Ethoxyresorufin-O-dealkylase activity in rat liver microsomes was markedly inhibited by PBYO and PBO, partly by PBYOL, but not by PBA.
Kitamura
Shigeyuki
S
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Minami-ku, Hiroshima, Japan.
Kohno
Yoichi
Y
Okamoto
Yuji
Y
Takeshita
Mitsuhiro
M
Ohta
Shigeru
S
D000480:Alkynes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002074:Butanones / Q000737:chemistry / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
C454401:4-phenyl-3-butyn-2-one; D000480:Alkynes; D002074:Butanones; D004791:Enzyme Inhibitors; D007659:Ketones; D009249:NADP; C025383:benzylideneacetone; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1