Concordant up‐regulation of cytochrome P450 Cyp3a11, testosterone oxidation and androgen receptor expression in mouse brain after xenobiotic treatment

Abstract

Inactivation of testosterone by specific hydroxylations is a main function of cytochrome P450 (P450, CYP) in the brain. Recent data imply that induction of brain P450s by neuroactive drugs alters steroid hormone levels and endocrine signalling, giving rise to endocrine disorders. In this study, we investigated this drug–hormone crosstalk in mouse brain. Phenytoin led to a significant increase of 2α‐, 2β‐, 6β‐, 16α‐ and 16β‐hydroxytestosterones, while 6α‐ and 15α‐hydroxytestosterones showed no significant alteration of their metabolism compared with untreated controls. Inhibition of testosterone hydroxylation using the chemical inhibitors orphenadrine, chloramphenicol, ketoconazole and nifedipine as well as antibodies against CYP3A‐ and 2B‐isoforms pointed to major role of Cyp3a11 and an only minor function of Cyp2b9/10 in mouse brain. Cyp3a11 revealed to be the major isoform affected by phenytoin. There was considerable overlap of Cyp3a11 and AR expression in neuronal structures of the limbic system, namely the hippocampus, amygdala, hypothalamus and thalamus. Phenytoin treatment led to an increase of both, Cyp3a11 and AR expression in the limbic system. Additionally, the coherence between CYP3A and AR expression was analysed in PC‐12 cells. Inhibition of phenytoin‐induced endogenous CYP3A2 and AR by ketoconazole led a reduction of their expression to basal levels. We conclude that Cyp3a11 plays a crucial role in directing drug action to hormonal response within the limbic system of mouse brain in a so‐called drug–hormone crosstalk.

Testosterone Depletion in Adult Male Rats Increases Mossy Fiber Transmission, LTP, and Sprouting in Area CA3 of Hippocampus

“…Therefore, addition of more androgen in vitro cannot elicit a detectable effect. This explanation has experimental support: cell surface expression of androgen receptors increases in response to reduced levels of circulating androgens (Kerr et al, 1995; Fargo et al, 2009; Meyer et al, 2009; Hsieh et al, 2011). Alternatively, increased androgen receptor expression at the cell surface of Gdx rats could be a compensatory response to increased excitability.…”

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

“…To our knowledge, this is the first report of expression of any CYP3A form in human amygdala at either the protein or mRNA level. However, cyp3a11 protein has been detected in murine amygdala (Meyer et al, 2009).…”

Cell Models for the Study of Sex Steroid Hormone Neurobiology

“…However, mRNA and protein expression for AR have been reported [138,139]. This difference in AR expression could be due to Glutamax supplementation, since the media and serum used are similar to what is used in our laboratory [138,139] (Table 2). …”