Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms
<i>CYP2D</i> enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/10/12/3472 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841526677021130752 |
|---|---|
| author | Przemysław J. Danek Władysława A. Daniel |
| author_facet | Przemysław J. Danek Władysława A. Daniel |
| author_sort | Przemysław J. Danek |
| collection | DOAJ |
| description | <i>CYP2D</i> enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (K<sub>i</sub> = 11.5 μM and K<sub>i</sub> = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and <i>CYP2D4</i> protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain <i>CYP2D4</i> mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur. |
| format | Article |
| id | doaj-art-c1a123288cef4b5f8a7721e5dca3eff3 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-c1a123288cef4b5f8a7721e5dca3eff32025-01-16T15:04:25ZengMDPI AGCells2073-44092021-12-011012347210.3390/cells10123472Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different MechanismsPrzemysław J. Danek0Władysława A. Daniel1Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, PolandDepartment of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland<i>CYP2D</i> enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (K<sub>i</sub> = 11.5 μM and K<sub>i</sub> = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and <i>CYP2D4</i> protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain <i>CYP2D4</i> mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.https://www.mdpi.com/2073-4409/10/12/3472iloperidoneprolonged administrationbrainlivercytochrome P450 2D expression/activity |
| spellingShingle | Przemysław J. Danek Władysława A. Daniel Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms Cells iloperidone prolonged administration brain liver cytochrome P450 2D expression/activity |
| title | Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms |
| title_full | Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms |
| title_fullStr | Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms |
| title_full_unstemmed | Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms |
| title_short | Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms |
| title_sort | long term treatment with atypical antipsychotic iloperidone modulates cytochrome p450 2d cyp2d expression and activity in the liver and brain via different mechanisms |
| topic | iloperidone prolonged administration brain liver cytochrome P450 2D expression/activity |
| url | https://www.mdpi.com/2073-4409/10/12/3472 |
| work_keys_str_mv | AT przemysławjdanek longtermtreatmentwithatypicalantipsychoticiloperidonemodulatescytochromep4502dcyp2dexpressionandactivityintheliverandbrainviadifferentmechanisms AT władysławaadaniel longtermtreatmentwithatypicalantipsychoticiloperidonemodulatescytochromep4502dcyp2dexpressionandactivityintheliverandbrainviadifferentmechanisms |