Eaton D L, Hamel D M
Department of Environmental Health, University of Washington, Seattle 98195.
Toxicol Appl Pharmacol. 1994 May;126(1):145-9. doi: 10.1006/taap.1994.1100.
Previous studies have demonstrated that dietary administration of butylated hydroxyanisole (BHA) and other phenolic antioxidants increases hepatic glutathione (GSH). The purpose of this study was to examine whether BHA increases GSH by increasing the activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in hepatic GSH biosynthesis. Male Swiss-Webster mice were fed BHA in the diet at various doses (0.05-0.75%, w/w, of diet) for 14 days. An additional study examined the effects of 0.75% BHA on hepatic GSH and GCS activity at 1, 4, 8, and 14 days, and at various times following cessation of the BHA diet. BHA increased both GSH and GCS activity in a dose- and time-dependent fashion. At the maximal dose of 0.75% BHA, hepatic GSH and GCS activity was increased by 1.5-fold and 2.1-fold, respectively, by Day 8, and remained at this level at Day 14. GSH was initially depleted at 1 day on the BHA diet, but had returned to control levels at Day 4. Upon removal of the BHA diet, both GCS and GSH returned to control values within 4 days. Hepatic cytosolic GCS activity from BHA-treated mice was inhibited by GSH in a manner similar to that of GCS from untreated mice. These data demonstrate that GCS activity is increased by BHA, and that this increase may be responsible for the elevation of hepatic GSH after BHA treatment observed previously. Whether the BHA-mediated increase in GCS activity is the result of enhanced transcriptional activation of the GCS gene, or results from stabilization of existing GCS enzyme activity, requires further investigation.
先前的研究表明，在饮食中给予丁基羟基茴香醚（BHA）和其他酚类抗氧化剂可增加肝脏中的谷胱甘肽（GSH）。本研究的目的是检验BHA是否通过增加γ-谷氨酰半胱氨酸合成酶（GCS）的活性来增加GSH，GCS是肝脏GSH生物合成中的限速酶。将雄性瑞士韦伯斯特小鼠在饮食中给予不同剂量（饮食的0.05 - 0.75%，w/w）的BHA，持续14天。另一项研究考察了0.75%BHA在1天、4天、8天和14天以及停止BHA饮食后的不同时间对肝脏GSH和GCS活性的影响。BHA以剂量和时间依赖性方式增加GSH和GCS活性。在最大剂量0.75%BHA时，到第8天肝脏GSH和GCS活性分别增加了1.5倍和2.1倍，并在第14天保持在该水平。在BHA饮食的第1天，GSH最初减少，但在第4天恢复到对照水平。去除BHA饮食后，GCS和GSH在4天内恢复到对照值。BHA处理小鼠的肝脏胞质GCS活性受到GSH的抑制，其方式与未处理小鼠的GCS相似。这些数据表明，BHA可增加GCS活性，这种增加可能是先前观察到的BHA处理后肝脏GSH升高的原因。BHA介导的GCS活性增加是GCS基因转录激活增强的结果，还是现有GCS酶活性稳定化的结果，需要进一步研究。
