Induction of metallothionein by steroids in rat primary hepatocyte cultures

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.