Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function
Cytochrome P450 is responsible for the metabolism of endogenous substrates, drugs and substances of abuse. The brain and nervous system regulate liver cytochrome P450 via neuroendocrine mechanisms, as shown in rodents. Cocaine exerts its addictive effects through the dopaminergic system, the functio...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1632 |
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| author | Joanna Jastrzębska Władysława Anna Daniel |
| author_facet | Joanna Jastrzębska Władysława Anna Daniel |
| author_sort | Joanna Jastrzębska |
| collection | DOAJ |
| description | Cytochrome P450 is responsible for the metabolism of endogenous substrates, drugs and substances of abuse. The brain and nervous system regulate liver cytochrome P450 via neuroendocrine mechanisms, as shown in rodents. Cocaine exerts its addictive effects through the dopaminergic system, the functioning of which undergoes changes during its continuous use. Therefore, it can be hypothesized that the regulation of cytochrome P450 by cocaine may also alter during the addiction process, cessation and relapse. We analyzed preclinical studies on the mechanisms of the pharmacological action of cocaine, the role of the brain’s dopaminergic system in the neuroendocrine regulation of cytochrome P450 and the in vitro and in vivo effects of cocaine on the cytochrome P450 expression/activity and hepatotoxicity. The results of passive cocaine administration indicate that cocaine affects liver cytochrome P450 enzymes (including those engaged in its own metabolism) via different mechanisms involving the expression of genes encoding cytochrome P450 enzymes and interaction with enzyme proteins. Thus, it may affect its own oxidative metabolism and the metabolism of endogenous substrates and other co-administered drugs and may lead to hepatotoxicity. Its effect depends on the specific cytochrome P450 enzyme affected, cocaine dosage, treatment duration and animal species. However, further complementary studies are needed to find out whether cocaine affects cytochrome P450 via the brain’s dopaminergic system. The knowledge of cocaine’s effect on cytochrome P450 function during the entire addiction process is still incomplete. There is a lack of information on the enzyme expression/activity in animals self-administering cocaine (addicted), in those withdrawn after cocaine self-administration, and during relapse in animals previously addicted; furthermore, there is no such information concerning humans. The subject of cytochrome P450 regulation by cocaine during the addiction process is an open issue, and addressing this topic may help in the treatment of drug abuse patients. |
| first_indexed | 2024-03-09T12:19:02Z |
| format | Article |
| id | doaj.art-9abafebbe62440289af9278f0bc6fb78 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:19:02Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9abafebbe62440289af9278f0bc6fb782023-11-30T22:43:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242163210.3390/ijms24021632Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver FunctionJoanna Jastrzębska0Władysława Anna 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, PolandCytochrome P450 is responsible for the metabolism of endogenous substrates, drugs and substances of abuse. The brain and nervous system regulate liver cytochrome P450 via neuroendocrine mechanisms, as shown in rodents. Cocaine exerts its addictive effects through the dopaminergic system, the functioning of which undergoes changes during its continuous use. Therefore, it can be hypothesized that the regulation of cytochrome P450 by cocaine may also alter during the addiction process, cessation and relapse. We analyzed preclinical studies on the mechanisms of the pharmacological action of cocaine, the role of the brain’s dopaminergic system in the neuroendocrine regulation of cytochrome P450 and the in vitro and in vivo effects of cocaine on the cytochrome P450 expression/activity and hepatotoxicity. The results of passive cocaine administration indicate that cocaine affects liver cytochrome P450 enzymes (including those engaged in its own metabolism) via different mechanisms involving the expression of genes encoding cytochrome P450 enzymes and interaction with enzyme proteins. Thus, it may affect its own oxidative metabolism and the metabolism of endogenous substrates and other co-administered drugs and may lead to hepatotoxicity. Its effect depends on the specific cytochrome P450 enzyme affected, cocaine dosage, treatment duration and animal species. However, further complementary studies are needed to find out whether cocaine affects cytochrome P450 via the brain’s dopaminergic system. The knowledge of cocaine’s effect on cytochrome P450 function during the entire addiction process is still incomplete. There is a lack of information on the enzyme expression/activity in animals self-administering cocaine (addicted), in those withdrawn after cocaine self-administration, and during relapse in animals previously addicted; furthermore, there is no such information concerning humans. The subject of cytochrome P450 regulation by cocaine during the addiction process is an open issue, and addressing this topic may help in the treatment of drug abuse patients.https://www.mdpi.com/1422-0067/24/2/1632cocainedopaminergic systemaddictionlivercytochrome P450hepatotoxicity |
| spellingShingle | Joanna Jastrzębska Władysława Anna Daniel Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function International Journal of Molecular Sciences cocaine dopaminergic system addiction liver cytochrome P450 hepatotoxicity |
| title | Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function |
| title_full | Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function |
| title_fullStr | Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function |
| title_full_unstemmed | Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function |
| title_short | Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function |
| title_sort | cocaine induced time dependent alterations in cytochrome p450 and liver function |
| topic | cocaine dopaminergic system addiction liver cytochrome P450 hepatotoxicity |
| url | https://www.mdpi.com/1422-0067/24/2/1632 |
| work_keys_str_mv | AT joannajastrzebska cocaineinducedtimedependentalterationsincytochromep450andliverfunction AT władysławaannadaniel cocaineinducedtimedependentalterationsincytochromep450andliverfunction |