Gebhardt R, Beck H
Physiologisch-Chemisches Institut, University of Tübingen, Germany.
Lipids. 1996 Dec;31(12):1269-76. doi: 10.1007/BF02587912.
Using primary rat hepatocyte cultures, the potency of several garlic-derived organosulfur compounds to inhibit cholesterol biosynthesis in toto as well as at early and late steps of this metabolic pathway was compared. Concerning early steps, allicin significantly inhibited incorporation of [14C]acetate into nonsaponifiable neutral lipids already at concentrations as low as 10 microM, while diallyl disulfide and allyl mercaptan were effective above 100 microM only. Likewise, inhibition in response to the two vinyl-dithiins started at 500 microM. If [14C]acetate was replaced by [14C]mevalonate, inhibition due to allicin, diallyl disulfide, and allyl mercaptan disappeared suggesting that HMGCoA-reductase was the target of inhibition. In contrast, for the vinyl-dithiins a stimulation of mevalonate incorporation was found. Concerning the late step, the potency to exert accumulation of lanosterol presumably by inhibiting lanosterol 14 alpha-demethylase decreased in the order allicin > diallyl disulfide > allyl mercaptan = 1,3-vinyl-dithiin >> 1,2-vinyldithiin, the effect of the latter compound being close to zero. With respect to the total inhibition of [14C]acetate labeling of cholesterol, the half-maximal effective concentration-value of allicin was determined to be 17 +/- 2 microM compared to 64 +/- 7 microM for diallyl disulfide and to 450 +/- 20 microM for allyl mercaptan. Cytotoxicity as determined by the lactate dehydrogenase leakage assay was slightly higher for the two vinyl-dithiins than for diallyl disulfide and allyl mercaptan, but was apparent only at concentrations higher than 10 mM and, consequently, was irrelevant for the effects described. These results demonstrate that different garlic-derived organosulfur compounds interfere differently with cholesterol biosynthesis and, thus, may provoke multiple inhibition of this metabolic pathway in response to garlic consumption. The fact that allicin was the most effective inhibitor argues against the possibility that its degradation products, namely diallyl disulfide or allyl mercapatan, might mediate its effects, a possibility that might be true, however, in the case of the vinyl-dithiins.
利用原代大鼠肝细胞培养物，比较了几种大蒜衍生的有机硫化合物在整体上以及在该代谢途径的早期和晚期步骤中抑制胆固醇生物合成的能力。关于早期步骤，大蒜素在低至10微摩尔的浓度下就显著抑制了[14C]乙酸盐掺入非皂化中性脂质中，而二烯丙基二硫化物和烯丙基硫醇仅在100微摩尔以上才有效。同样，两种乙烯基二硫醚的抑制作用在500微摩尔时开始。如果用[14C]甲羟戊酸代替[14C]乙酸盐，大蒜素、二烯丙基二硫化物和烯丙基硫醇引起的抑制作用消失，这表明3-羟基-3-甲基戊二酰辅酶A还原酶是抑制的靶点。相反，对于乙烯基二硫醚，发现甲羟戊酸掺入受到刺激。关于晚期步骤，可能通过抑制羊毛甾醇14α-脱甲基酶来促使羊毛甾醇积累的能力按以下顺序降低：大蒜素>二烯丙基二硫化物>烯丙基硫醇 = 1,3-乙烯基二硫醚 >> 1,2-乙烯基二硫醚，后一种化合物的作用接近零。关于对胆固醇的[14C]乙酸盐标记的总抑制作用，大蒜素的半数有效浓度值确定为17±2微摩尔，而二烯丙基二硫化物为64±7微摩尔，烯丙基硫醇为450±20微摩尔。通过乳酸脱氢酶泄漏试验测定的细胞毒性，两种乙烯基二硫醚略高于二烯丙基二硫化物和烯丙基硫醇，但仅在高于10毫摩尔的浓度下才明显，因此与所述效应无关。这些结果表明，不同的大蒜衍生有机硫化合物对胆固醇生物合成的干扰不同，因此，食用大蒜可能会对该代谢途径产生多重抑制作用。大蒜素是最有效的抑制剂这一事实排除了其降解产物（即二烯丙基二硫化物或烯丙基硫醇）可能介导其作用的可能性，然而，在乙烯基二硫醚的情况下，这种可能性可能是成立的。
