Anti‐epileptic drug phenytoin enhances androgen metabolism and androgen receptor expression in murine hippocampus

Abstract

Epilepsy is very often related to strong impairment of neuronal networks, particularly in the hippocampus. Previous studies of brain tissue have demonstrated that long-term administration of the anti-epileptic drug (AED) phenytoin leads to enhanced metabolism of testosterone mediated by cytochrome P450 (CYP) isoforms. Thus, we speculate that AEDs affect androgen signalling in the hippocampus. In the present study, we investigated how the AED phenytoin influences the levels of testosterone, 17b-oestradiol, and androgen receptor (AR) in the hippocampus of male C57Bl/6J mice. Phenytoin administration led to a 61.24% decreased hippocampal testosterone level as compared with controls, while serum levels were slightly enhanced. 17b-Oestradiol serum level was elevated 2.6-fold. Concomitantly, the testosterone metabolizing CYP isoforms CYP3A11 and CYP19 (aromatase) have been found to be induced 2.4-and 4.2-fold, respectively. CYP3A-mediated depletion of testosterone-forming 2b-, and 6b-hydroxytestosterone was significantly enhanced. Additionally, AR expression was increased 2-fold (mRNA) and 1.8-fold (protein), predominantly in the CA1 region. AR was shown to concentrate in nuclei of CA1 pyramidal neurons. We conclude that phenytoin affects testosterone metabolism via induction of CYP isoforms. The increased metabolism of testosterone leading to augmented androgen metabolite formation most likely led to enhanced expression of CYP19 and AR in hippocampus. Phenytoin obviously modulates the androgen signalling in the hippocampus.

Antiepileptic Drugs Affect Neuronal Androgen Signaling via a Cytochrome P450-Dependent Pathway

“…This observation indicates a fundamental difference between brain P450 and that in liver, in which a constitutive heme pool is provided (Giger and Meyer, 1983). Nevertheless, previous studies in rodents encouraged the concept that brain P450s have a prominent function in steroid hormone regulation (Rosenbrock et al, 1999;Wang et al, 2000;Meyer et al, 2006).…”

“…It seems that CYP3A11 itself has influence on AR transcription, whereas AR activation was shown to be dependent on the availability of both CYP3A11 and its substrate testosterone. Previous studies demonstrate that conversion of testosterone to its hydroxylated metabolites is substantially increased in brain as a consequence of phenytoin administration (Rosenbrock et al, 1999;Meyer et al, 2006). In addition, this CYP3A11-dependent depletion of testosterone in mouse hippocampus is accompanied by increased AR expression (Meyer et al, 2006).…”

“…It has been shown that enzymatic activity of brain P450 is dependent on the availability of the prosthetic group heme (Meyer et al, 2002(Meyer et al, , 2005 and that glial and neuronal P450 have different function (Meyer et al, 2004). Some studies indicate that brain P450 may act in mediation of steroid hormone signaling (Wang et al, 2000;Hagemeyer et al, 2003;Meyer et al, 2006). We hypothesize that brain P450 has functions beyond drug metabolism.…”

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

“…Moreover, a markedly reduced serum bioavailable testosterone levels and sexual function was reported (Herzog et al, 2006). Two-week phenytoin treatment has been shown to affect the hippocampal levels of testosterone, CYP isoforms, and AR expression in a mouse model (Meyer et al, 2006). The increased metabolism of testosterone leading to augmented androgen metabolite formation most likely led to enhanced expression of CYP19 and AR in hippocampus.…”

Nuclear receptors CAR and PXR in the regulation of hepatic metabolism

“…UGT1A1 and CYP3A, which can both be regulated by CAR and PXR, are known to act upon estrogen leading to excretion (Hammond et al 1997;Sugatani et al 2001;Sugatani et al 2005). In addition, the CAR activator phenytoin has been found to regulate androgen and testosterone metabolism through CYP3A in the mouse brain (Rosenbrock et al 1999;Meyer et al 2006). In the liver, CYP3A can also metabolize testosterone and progesterone (Yamazaki and Shimada 1997).…”