Dehydroepiandrosterone Prevents H(2)O(2)-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H(2)O(2). The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H(2)O(2)-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H(2)O(2)-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H(2)O(2)-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H(2)O(2)-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.