The CYP A genes are regulated
The CYP3A genes are regulated physiologically by glucocorticosteroids, growth hormone, thyroid hormones and cytokines [13, 20, 30]. It has been shown that glucocorticoid receptor (GR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and vitamin D receptor (VDR) play an important role in the regulation of CYP3A genes [2, 6]. Both PXR and CAR act as dimers with retinoid Ponesimod X receptor (RXR). GR may contribute to CYP3A induction via direct or indirect molecular mechanism, including functional cross talk between GR-, PXR- and CAR-signaling pathways [4, 19].
Our recent studies demonstrated that a lesion or activation of the tuberoinfundibular or the mesolimbic pathway of the brain dopaminergic system affects liver CYP activity and protein level (CYP1A, CYP2B, CYP2C11 and CYP3A), as well as blood plasma concentration of the respective pituitary hormones (growth hormone, triiodothyronine and corti-costerone) in the rat. Thus, the neuroleptic drugs that block dopaminergic D2 receptors may affect CYP expression via their action on the brain dopaminergic system, having an impact on the endocrine and immune systems [33., 34., 35., 37, 38].
Some literature data indicate that neuroleptics affect CYP3A activity. Two-week treatment with clozapine in a dose substantially exceeding the pharmacological/therapeutic one (114mg/kg/day) increased the level and activity of CYP3A1 in rats, whereas sulpiride (137mg/kg/day) and remoxipride (31mg/kg/ day) produced a decrease in the level of this enzyme . Another study conducted by Tateishi et al. , who administered chlorpromazine and thioridazine in a relatively high dose of 20mg/kg intraperitoneally (ip) for 4 days, showed that chlorpromazine did not change the total level of CYP, but induced CYP3A, whereas thioridazine reduced the total level of CYP, as well as the level and activity of CYP3A. Our previous study showed that some antidepressant drugs administered in pharmacological doses for one-day or two weeks to rats affect CYP3A level and activity . Moreover, a few clinical studies suggest that phenothiazine neuroleptics may cause the CYP induction in the human liver [9, 15, 23].
Materials and Methods
Results The obtained results showed that the investigated neuroleptics directly inhibited CYP3A activity in rats, shown as inhibition of the rate of CYP3A-specific reactions, i.e., the 2β- and the 6β-hydroxylation of testosterone by the drug added to control liver microsomes in vitro (Model I). Thioridazine was a more potent inhibitor of the reactions studied, while chlorpromazine and sertindole were weaker in this respect (Tab. 1). The inhibitory effects of the tested neuroleptics were moderate (thioridazine: Ki=50), modest (chlorpromazine and sertindole: Ki=77 and 81μM, respectively) or weak (promazine and haloperidol: Ki=161 and 177μM, respectively) (Tab. 1). Risperidone produced the weakest inhibitory effect on CYP3A activity (Ki=214μM) (Tab. 1). Our study demonstrated that from the investigated neuroleptics only chlorpromazine exerted a significant effect on CYP3A activity when they were given to rats for one day (i.e., for 24h; Model II) (Fig. 1). Chlorpromazine elevated CYP3A activity to 192% of the control. After two-week treatment with the tested neuroleptics (Model III), thioridazine significantly decreased the activity of CYP3A (to 43% of the control), while risperidone increased CYP3A activity (to 161% of the control) (Fig. 2). The other neuroleptics studied did not produce any significant effect when administered in vivo for two weeks. As shown in Figures 3A and B, the changes observed in CYP3A protein level after chronic treatment with neuroleptics corresponded well with those related to the enzyme activity. Thioridazine visibly diminished CYP3A protein level to 66% of the control, while risperidone significantly elevated CYP3A protein level to 137% of the control.