The cytochrome P450 (CYP) enzyme system plays an important role in regulating neurophysiological processes within the central nervous system through its involvement in neurosteroid metabolism. Phenytoin (PHT), a commonly used antiepileptic drug, has been associated with adverse neuronal effects, which may result from its ability to induce CYP expression and alter testosterone (TES) metabolism in the hippocampus. Although the pregnane X receptor (PXR) is well recognized for its role in controlling hepatic CYP expression, our findings reveal that pregnenolone 16α-carbonitrile (PCN), a PXR agonist, exerts distinct regulatory effects on CYP expression in the liver compared with the hippocampus in mice. PCN administration increased the expression of CYP3A11 and CYP2B10 in the liver but led to a reduction of these enzymes in the hippocampus. Importantly, PCN treatment alleviated PHT-induced hippocampal neuronal damage, which was associated with suppressed TES metabolism in the hippocampus. Further mechanistic investigations demonstrated that the downregulation of hippocampal CYP expression and the protective effects of PCN against PHT-induced neurotoxicity were mediated by the glucocorticoid receptor rather than PXR, as confirmed through both genetic and pharmacological approaches. Overall, this study demonstrates that PCN can suppress CYP expression in the hippocampus and reduce PHT-induced neurotoxicity through a PXR-independent mechanism. These results indicate that glucocorticoids may offer a promising therapeutic approach for mitigating the neurological side effects associated with PHT treatment.
