The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain
The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this wo...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/22/13746 |
| _version_ | 1797465171946373120 |
|---|---|
| author | Anna Haduch Ewa Bromek Renata Pukło Joanna Jastrzębska Przemysław Jan Danek Władysława Anna Daniel |
| author_facet | Anna Haduch Ewa Bromek Renata Pukło Joanna Jastrzębska Przemysław Jan Danek Władysława Anna Daniel |
| author_sort | Anna Haduch |
| collection | DOAJ |
| description | The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug–drug interactions. |
| first_indexed | 2024-03-09T18:18:41Z |
| format | Article |
| id | doaj.art-783a65cc843f40aa9f4e77f8e5dcfaaf |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:18:41Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-783a65cc843f40aa9f4e77f8e5dcfaaf2023-11-24T08:32:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221374610.3390/ijms232213746The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and BrainAnna Haduch0Ewa Bromek1Renata Pukło2Joanna Jastrzębska3Przemysław Jan Danek4Władysława Anna Daniel5Department 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, PolandDepartment 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, PolandDepartment 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, PolandThe CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug–drug interactions.https://www.mdpi.com/1422-0067/23/22/13746CP-101,606CYP2Dactivity/expressionliverbrainchronic treatment |
| spellingShingle | Anna Haduch Ewa Bromek Renata Pukło Joanna Jastrzębska Przemysław Jan Danek Władysława Anna Daniel The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain International Journal of Molecular Sciences CP-101,606 CYP2D activity/expression liver brain chronic treatment |
| title | The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain |
| title_full | The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain |
| title_fullStr | The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain |
| title_full_unstemmed | The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain |
| title_short | The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain |
| title_sort | effect of the selective n methyl d aspartate nmda receptor glun2b subunit antagonist cp 101 606 on cytochrome p450 2d cyp2d expression and activity in the rat liver and brain |
| topic | CP-101,606 CYP2D activity/expression liver brain chronic treatment |
| url | https://www.mdpi.com/1422-0067/23/22/13746 |
| work_keys_str_mv | AT annahaduch theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT ewabromek theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT renatapukło theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT joannajastrzebska theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT przemysławjandanek theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT władysławaannadaniel theeffectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT annahaduch effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT ewabromek effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT renatapukło effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT joannajastrzebska effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT przemysławjandanek effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain AT władysławaannadaniel effectoftheselectivenmethyldaspartatenmdareceptorglun2bsubunitantagonistcp101606oncytochromep4502dcyp2dexpressionandactivityintheratliverandbrain |