Donohue Terrence M, Curry-McCoy Tiana V, Todero Sandra L, White Ronda L, Kharbanda Kusum K, Nanji Amin A, Osna Natalia A
Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska 68105, USA.
Alcohol Clin Exp Res. 2007 Jun;31(6):1053-60. doi: 10.1111/j.1530-0277.2007.00393.x. Epub 2007 Apr 11.
L-Buthionine (S,R) sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and has been used as an effective means of depleting glutathione from cells and tissues. Here we investigated whether treatment with BSO enhanced ethanol-induced liver injury in mice.
Female C57Bl/6 mice were pair fed with control and ethanol-containing liquid diets in which ethanol was 29.2% of total calories. During the final 7 days of pair feeding, groups of control-fed and ethanol-fed mice were given 0, 5 or 7.6 mM BSO in the liquid diets.
Compared with controls, ethanol given alone decreased total liver glutathione. This effect was exacerbated in mice given ethanol with 7.6 mM BSO, causing a 72% decline in hepatic glutathione. While ethanol alone caused no decrease in mitochondrial glutathione, inclusion of 7.6 mM BSO caused a 2-fold decline compared with untreated controls. L-Buthionine (S,R) sulfoximine did not affect ethanol consumption, but serum ethanol levels in BSO-treated mice were nearly 6-fold lower than in mice given ethanol alone. The latter decline in serum ethanol was associated with a significant elevation in the specific activities of cytochrome P450 2E1 and alcohol dehydrogenase in livers of BSO-treated animals. Ethanol consumption caused a 3.5-fold elevation in serum alanine aminotransferase levels but the enzyme fell to control levels when BSO was included in the diet. L-Buthionine (S,R) sulfoximine administration also attenuated ethanol-induced steatosis, prevented the leakage of lysosomal cathepsins into the cytosol, and prevented the ethanol-elicited decline in proteasome activity.
L-Buthionine (S,R) sulfoximine, administered with ethanol, significantly depleted hepatic glutathione, compared with controls. However, despite the decrease in hepatic antioxidant levels, liver injury by ethanol was alleviated, due, in part, to a BSO-elicited acceleration of ethanol metabolism.
L-丁硫氨酸（S，R）亚砜亚胺（BSO）是谷胱甘肽生物合成的抑制剂，已被用作从细胞和组织中消耗谷胱甘肽的有效手段。在此，我们研究了用BSO处理是否会增强乙醇诱导的小鼠肝损伤。
将雌性C57Bl/6小鼠成对喂食对照液体饮食和含乙醇的液体饮食，其中乙醇占总热量的29.2%。在成对喂食的最后7天，给对照喂养和乙醇喂养的小鼠组在液体饮食中分别给予0、5或7.6 mM的BSO。
与对照组相比，单独给予乙醇会降低肝脏总谷胱甘肽水平。在给予乙醇和7.6 mM BSO的小鼠中，这种效应会加剧，导致肝脏谷胱甘肽下降72%。虽然单独给予乙醇不会使线粒体谷胱甘肽减少，但加入7.6 mM BSO会使其比未处理的对照组下降2倍。L-丁硫氨酸（S，R）亚砜亚胺不影响乙醇消耗，但经BSO处理的小鼠血清乙醇水平比单独给予乙醇的小鼠低近6倍。血清乙醇水平的下降与经BSO处理动物肝脏中细胞色素P450 2E1和乙醇脱氢酶的比活性显著升高有关。乙醇消耗使血清丙氨酸转氨酶水平升高3.5倍，但当饮食中加入BSO时，该酶水平降至对照水平。给予L-丁硫氨酸（S，R）亚砜亚胺还可减轻乙醇诱导的脂肪变性，防止溶酶体组织蛋白酶泄漏到细胞质中，并防止乙醇引起的蛋白酶体活性下降。
与对照组相比，与乙醇一起给予L-丁硫氨酸（S，R）亚砜亚胺可显著消耗肝脏谷胱甘肽。然而，尽管肝脏抗氧化剂水平降低，但乙醇引起的肝损伤得到缓解，部分原因是BSO引起的乙醇代谢加速。
