The effect of glucocorticoids on epidermal growth factor (EGF)-induced expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. A significant suppression of the EGF-induced expression of 12-lipoxygenase was observed in cells pretreated with 1 microM dexamethasone for 2 hr. The same pretreatment for 8 hr resulted in 55 and 54% inhibition of EGF-induced 12-lipoxygenase activity and mRNA expression, respectively. Cortisol, but not sex and mineral steroids, had a similar inhibitory effect. The glucocorticoid antagonist RU486 completely blocked the inhibitory effect of dexamethasone, suggesting that the action of dexamethasone was mediated through the ligation of glucocorticoid receptors. The results indicated that pretreatment of A431 cells with glucocorticoids resulted in a down-regulation of the EGF-induced expression of 12-lipoxygenase at the mRNA and enzyme activity level, which was mediated through glucocorticoid receptor activation.