The Atypical Antipsychotic Lurasidone Affects Brain but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schizophrenia

Abstract

The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg/kg ip.) for two weeks. The activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1'-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of CYP2D1 without affecting that of CYP2D2, CYP2D3, CYP2D4, and CYP2D5. In conclusion, lurasidone regulates brain (but not liver) CYP2D activity/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures.

Keywords: brain; cytochrome P450 2D (CYP2D); enzyme expression and activity; liver; lurasidone.

Figure 1

The influence of the two-week treatment with lurasidone on the CYP2D activity measured in microsomes derived from the selected brain structures or liver. The presented values are the means ± S.E.M. of 15 samples (from 15 animals) for the cerebellum, remainder of brain, and the liver; of 7 samples (each sample contained 2 pooled brain structures from 2 animals) for the frontal cortex; brain stem, striatum, and hippocampus; and of 5 samples (each sample contained 3 pooled brain structures from 3 animals) for the hypothalamus, nucleus accumbens, and substantia nigra. Student’s t-test: * p < 0.05; ** p < 0.01 vs. control group. FCx—the frontal cortex, St—the striatum, NA—the nucleus accumbens, Hp—the hippocampus, Ht—the hypothalamus, Bs—the brain stem, SN—the substantia nigra, CB—the cerebellum, and RM—the remainder.

Figure 2

The effect of two-week treatment with lurasidone on the CYP2D protein levels measured in microsomes derived from the selected brain structures or liver. The presented values are the means ± S.E.M. of 15 samples (from 15 animals) for the cerebellum, remainder of brain, and the liver; of 7 samples (each sample contained 2 pooled brain structures from 2 animals) for the frontal cortex, brain stem, striatum, and hippocampus; or of 5 samples (each sample contained 3 pooled brain structured from 3 animals) for the hypothalamus, nucleus accumbens, and substantia nigra. The representative CYP2D protein bands of the Western blot analysis are shown. Brain or liver microsomal protein (10 µg) was subjected to Western blot analysis. cDNA-expressed CYP2D4 protein (Bactosomes) and cDNA-expressed CYP2D6 protein (Supersomes) was used as a positive control. Student’s t-test: * p < 0.05 vs. control group. FCx—the frontal cortex, St—the striatum, NA—the nucleus accumbens, Hp—the hippocampus, Ht—the hypothalamus, BS—the brain stem, SN—the substantia nigra, CB—the cerebellum, and RM—the remainder.

Figure 3

The influence of two-week treatment with lurasidone on the mRNA levels of the CYP2D1, CYP2D2, CYP2D3, CYP2D4, and CYP2D5 genes in the liver. The results are expressed as the fold change compared to the ACTB housekeeping gene. The presented values are the mean fold change quantified by the comparative delta–delta Ct method for the control and lurasidone-treated rats (mean ± S.E.M. of 10 sample). Student’s t-test: ** p < 0.01 vs. control group.