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  • Our present data show that

    2020-11-19

    Our present data show that neuroleptics can affect CYP3A via a direct interaction with the enzyme and a significant indirect mechanism (enzyme regulation) produced in vivo. The obtained results revealed interactions of the neuroleptics (added in vitro to control liver microsomes, Model I) with rat CYP3A, which led to a decrease in the enzyme activity. The Ki values obtained for thioridazine (50μM) and chlorpromazine (77μM) may be of importance in vivo regarding the dosage and the pharmacokinetics of these drugs. Phe-nothiazine neuroleptics are administered in relatively high doses compared to other neuroleptics, and being taken up by the tissue, reach concentrations that are 10–15 times higher in the liver than in blood plasma [32, 36]. Therefore, phenothiazine neuroleptics whose Ki values are below 100μM, in particular thioridazine, may reach the hepatic level close to the respective Ki values and are expected to decrease CYP3A activity in vivo. These findings may be of physiological, pharmacological or toxicological significance, considering the catalytic competence of this enzyme (the metabolism of steroids, drugs and toxins). As to the other investigated neuroleptics, the calculated Ki values are above their pharmacological/therapeutic concentrations. Sertindole (Ki=81μM) is not likely to directly inhibit the activity of CYP3A when administered in vivo, considering its low pharmacological/therapeutic doses and concentrations [31]. The observed inhibitory potency of the investigated neuroleptics on CYP3A was similar to that of the previously studied antidepressants (Ki=42–212μM) [8]. Of the investigated neuroleptics only chlorpromazine significantly elevated the CYP3A activity when administered in vivo for one day (i.e., for 24h; Model II). The obtained results are in agreement with literature data showing that this neuroleptic is able to induce CYP enzymes, including CYP3A, in rats after high doses and in humans [9, 15, 23, 28]. As mentioned in the introduction, our recent studies provided direct evidence for the important role of the Vacuolin-1 dopaminergic system in the regulation of CYP expression in rat liver [33., 34., 35., 37, 38]. Accordingly, the neuroleptic drugs that block dopaminergic D2 receptors may influence the secretion of pituitary hormones (e.g., GH, ACTH, TSH) which directly (GH) or indirectly (ACTH → corticosterone, TSH → thyroid hormones) activate nuclear/cytosolic receptors controlling CYP genes, including CYP3A. Therefore, a possible cause of the inhibitory effects on CYP3A expression observed in the case of thioridazine given in vivo (Model III) may be their influence on CYP3A gene regulation via blockade of dopaminergic D2 receptors in the pituitary and, in consequence, the inhibition of GH and/or corticosterone secretion. The above-mentioned hormones play an important role in the positive regulation of rat CYP3A [13, 30]. The results obtained in the present study are also in line with other observations indicating down-regulation of CYP3A in rats after 2-week treatment with the selective antagonists of dopaminergic D2 receptors, sulpiride and remoxipride and after 4-day treatment with the less specific dopaminergic D2 receptor-blocking neuroleptic – thioridazine [24, 28]. However, the other phenothiazines tested, i.e., promazine and chlorpromazine, do not produce any significant effect on CYP3A activity when administered in vivo for two weeks. The lack of effect of promazine on CYP3A may steam from the fact that of the phenothiazines tested, promazine is the weakest blocker of the dopaminergic D2 receptor [3]. Accordingly, the effect of promazine on the secretion of pituitary hormones regulating the CYP3A gene may be negligible. In addition, this neuroleptic shows the ability to induce rat cytochrome P450 [17] and human CYP3A4 (our unpublished data) at the hepatocyte level, which may mask its inhibitory effect on CYP3A regulation via the neuroendocrine system. On the other hand, chronic treatment with chlorpromazine, which is a potent antagonist of the dopaminergic D2 receptor [3], does not affect CYP3A activity. Like in the case of promazine, the D2 receptor-mediated effect of chlorpromazine on the hormonal regulation of CYP3A (down-regulation) may be masked by the inducing effect of chlorpromazine on cytochrome P450 at the level of the liver. It was shown previously that chlorpromazine induced CYP3A in the rat [28]. In the case of risperidone, which affected CYP3A activity and protein level only upon chronic administration, some influence of the drug on the enzyme regulation may be suggested.