Bracken W M, Klaassen C D
Toxicol Appl Pharmacol. 1987 Mar 15;87(3):381-8. doi: 10.1016/0041-008x(87)90242-0.
The purpose of this study was to characterize the induction of metallothionein (MT) by steroids in rat primary hepatocyte cultures. Comparison of the characteristics of MT induction by a steroid (dexamethasone) to that by metals (Zn and Cd), examination of the involvement of the glucocorticoid receptor in the steroid induction of MT, and determination of the potency and effectiveness of a number of steroids were studied. In general, the patterns of MT induction by metals and steroids were quite different. For metals, the maximal MT induction (12- to 39-fold) was limited by toxicity whereas for steroids, a plateau in MT induction (fivefold) occurred at noncytotoxic concentrations. Steroids elicited an increase in MT at concentrations that were one-hundredth to one-thousandth less than that of metals. A combination of metal and steroid increased the induction of MT to a level higher than achieved by metal or steroid alone. The effectiveness of steroids at inducing MT was related to their ability to induce a specific glucocorticoid effect, induction of tyrosine aminotransferase. For specific classes of steroids, synthetic glucocorticoids were more potent than the metals in inducing MT, but endogenous glucocorticoids, mineralocorticoids, androgens, and estrogens were less potent than the metals. The concentration of corticosterone, the major endogenous glucocorticoid of rats, required to induce MT in hepatocytes was 100 times higher than concentrations achievable in the plasma of rats. In conclusion, in rat hepatocytes dexamethasone was a more potent but less effective inducer of MT than Zn or Cd; synthetic glucocorticoids were more potent but endogenous adrenalcorticoids (i.e., glucocorticoids, mineralocorticoids, androgens, and estrogens) were both less potent and less effective inducers of MT than were metals, suggesting that glucocorticoids may not be the mediator for stress-induced MT induction; and induction of MT by steroids correlated well with the induction of tyrosine aminotransferase, supporting the involvement of a hormone-receptor complex in the induction of MT by steroids.
本研究的目的是在大鼠原代肝细胞培养物中表征类固醇对金属硫蛋白（MT）的诱导作用。将一种类固醇（地塞米松）诱导MT的特征与金属（锌和镉）诱导MT的特征进行比较，研究糖皮质激素受体在类固醇诱导MT过程中的作用，并测定多种类固醇的效力和效果。总体而言，金属和类固醇诱导MT的模式有很大不同。对于金属，MT的最大诱导倍数（12至39倍）受毒性限制，而对于类固醇，在非细胞毒性浓度下MT诱导出现平台期（五倍）。类固醇诱导MT增加时的浓度比金属低百分之一至千分之一。金属和类固醇联合使用可使MT的诱导水平高于单独使用金属或类固醇时达到的水平。类固醇诱导MT的效力与其诱导特定糖皮质激素效应（酪氨酸转氨酶诱导）的能力相关。对于特定类别的类固醇，合成糖皮质激素在诱导MT方面比金属更有效，但内源性糖皮质激素、盐皮质激素、雄激素和雌激素比金属效力更低。诱导大鼠肝细胞中MT所需的主要内源性糖皮质激素皮质酮的浓度比大鼠血浆中可达到的浓度高100倍。总之，在大鼠肝细胞中，地塞米松是比锌或镉更有效的MT诱导剂，但效力较低；合成糖皮质激素效力更高，但内源性肾上腺皮质激素（即糖皮质激素、盐皮质激素、雄激素和雌激素）在诱导MT方面比金属效力更低且效果更差，这表明糖皮质激素可能不是应激诱导MT的介质；类固醇诱导MT与酪氨酸转氨酶的诱导密切相关，支持激素 - 受体复合物参与类固醇诱导MT的过程。
