Okada K, Yagasaki K, Mochizuki T, Takagi K, Irikura T
Biochem Pharmacol. 1985 Sep 15;34(18):3361-7. doi: 10.1016/0006-2952(85)90358-2.
The effects of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), a new hypolipidemic agent, on serum cholesterol level and cholesterol biosynthesis were studied in normolipidemic rats. KCD-232 dose-dependently reduced the serum cholesterol level. The in vivo incorporation of [14C]-acetate and 3H from [3H]water into liver digitonin-precipitable sterols was inhibited by oral administration of KCD-232, while that of [14C]mevalonic acid into the sterols was not inhibited. Hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity was suppressed significantly by the oral administration of the drug. A KCD-232 metabolite, 4-(4'-chlorobenzyloxy)benzoic acid (MII), strongly inhibited [14C]acetate incorporation and weakly inhibited [14C]mevalonic acid incorporation into the sterols in liver slices. MII also significantly inhibited the sterol synthetic rate measured with [3H]water and the HMG-CoA reductase activity in dispersed hepatocytes. MII and its CoA thioester (MII-CoA) inhibited the incorporation of [14C]acetate, [14C]acetyl-CoA and [14C]HMG-CoA into nonsaponifiable lipids in a cell-free enzyme system from rat liver. MII-CoA further showed a weak inhibition of [14C]-mevalonic acid incorporation into nonsaponifiable lipids in the system, while MII showed no effect on mevalonic acid incorporation. These results indicate that KCD-232 possesses a major inhibitory site for sterol synthesis on HMG-CoA reductase due to both MII and MII-CoA, and a possible second site of action beyond mevalonic acid due to MII-CoA. The latter inhibitory site, however, is considered to play a minor role in the inhibition of sterol synthesis in vivo.
在正常血脂大鼠中研究了新型降血脂药物4-(4'-氯苄氧基)苄基烟酸酯(KCD-232)对血清胆固醇水平和胆固醇生物合成的影响。KCD-232剂量依赖性地降低血清胆固醇水平。口服KCD-232可抑制[14C]-乙酸盐和[3H]水中的3H在体内掺入肝洋地黄皂苷可沉淀甾醇，而[14C]甲羟戊酸掺入甾醇则未受抑制。口服该药物可显著抑制肝脏3-羟基-3-甲基戊二酰(HMG)-辅酶A还原酶活性。KCD-232的一种代谢产物4-(4'-氯苄氧基)苯甲酸(MII)强烈抑制[14C]乙酸盐掺入，并微弱抑制[14C]甲羟戊酸掺入肝切片中的甾醇。MII还显著抑制用[3H]水测定的甾醇合成速率以及分散肝细胞中的HMG-辅酶A还原酶活性。MII及其辅酶A硫酯(MII-CoA)在大鼠肝脏无细胞酶系统中抑制[14C]乙酸盐、[14C]乙酰辅酶A和[14C]HMG-辅酶A掺入不皂化脂质。MII-CoA在该系统中还对[14C]-甲羟戊酸掺入不皂化脂质表现出微弱抑制作用，而MII对甲羟戊酸掺入无影响。这些结果表明，由于MII和MII-CoA，KCD-232在HMG-辅酶A还原酶上具有甾醇合成的主要抑制位点，并且由于MII-CoA可能存在甲羟戊酸之外的第二个作用位点。然而，后一个抑制位点在体内甾醇合成抑制中被认为起次要作用。
