The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms

Abstract

Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16β; 2α and 16α; 2β and 6β, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose.

Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms

“…The observed decrease in the activity of liver CYP2D after the two-week iloperidone treatment corresponds well with the reduced CYP2D1, CYP2D2 and CYP2D4 protein levels in the rat liver microsomes and CYP2D1 , CYP2D2 and CYP2D4 mRNA levels, which indicates that the negative regulation of activity/expression of liver CYP2D enzymes by iloperidone proceeds at the transcriptional level. Although hepatic CYP2D levels are considered to be primarily influenced by genetic factors, recent studies indicate that their regulation at a transcriptional level is also possible by continuous treatment with some drugs, such as atypical neuroleptics, which has also been observed for asenapine [ 42 ].…”

“…The CYP2D protein levels in microsomes from the brains and livers of control and iloperidone-treated animals were quantified by Western blotting, as previously described [ 42 , 43 ]. Briefly, microsomal proteins (10 μg of brain and liver microsomes per each sample) were separated using an SDS polyacrylamide gel electrophoresis, and then the protein bands were transferred onto nitrocellulose membranes (Amersham Protran, Merck KGaA, Darmstadt, Germany).…”

The Effect of Chronic Iloperidone Treatment on Cytochrome P450 Expression and Activity in the Rat Liver: Involvement of Neuroendocrine Mechanisms

“…It has been documented that dopaminergic D 2 [12], adrenergic α 2 [13], and serotonergic 5-HT 1A and 5-HT 2C [15] receptors of the brain are engaged in the central neuroendocrine regulation of liver cytochrome P450. The action of iloperidone on dopaminergic, serotonergic, and adrenergic receptors may affect the neuroendocrine system and, in turn, the regulation of cytochrome P450 in the liver (discussed in [17]). The observed inhibitory effect of iloperidone on cytochrome P450 enzymes of the CYP1A, CYP2B, CYP2C, and CYP3A subfamilies may lead to pharmacokinetic (metabolic) interactions with concomitantly administered drugs.…”

“…The activity of CYP2E1 was estimated by measuring the rate of 6-hydroxylation of chlorzoxazone at a substance concentration of 200 µM and incubation time of 20 min. Chlorzoxazone and its metabolites were analyzed by HPLC with UV detection [17]. The activities of CYP2A, CYP2B, CYP2C11, and CYP3A were studied by measuring the rates of cytochrome P450 enzyme-specific reactions: 7α-, 16β-, 2α-, 16α-, 2β-, and 6β-hydroxylation of testosterone at a substrate concentration of 100 µM and incubation time of 15 min.…”

“…Considering the abovementioned possibilities of drug influence on cytochrome P450, in vitro models may be used to examine the direct and indirect peripheral mechanisms taking place in the liver (e.g., liver slices, hepatocyte cultures, liver microsomes, or cDNAexpressed CYPs). However, studying the drug effects on CYP regulation in the liver mediated by central mechanisms requires in vivo models, whereby the brain's nervous system (via its receptors located on hypothalamic endocrine cells) can act on peripheral endocrine glands and, in turn, on liver function [15][16][17].…”