Vol. 30, Issue 4, 414-420, April 2002

Reductive Metabolism of an ,-Ketoalkyne, 4-Phenyl-3-Butyn-2-One, by Rat Liver Preparations

Shigeyuki Kitamura, Yoichi Kohno, Yuji Okamoto, Mitsuhiro Takeshita, and Shigeru Ohta

Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Minami-ku, Hiroshima, Japan (S.K., Y.K., Y.O., S.O.); and Tohoku College of Pharmacy, Aoba-ku, Sendai, Japan (M.T.)

The reduction of the triple bond and carbonyl group of an ,-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-glycyrrhetinic acid but not -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.