In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking
Purpose. The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP+) and reduced haloperidol pyridinium (RHP+). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural ana...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-10-01
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| Series: | Journal of Pharmacy & Pharmaceutical Sciences |
| Online Access: | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/16594 |
| _version_ | 1797763324308357120 |
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| author | Jim Fang Jiuxue Song |
| author_facet | Jim Fang Jiuxue Song |
| author_sort | Jim Fang |
| collection | DOAJ |
| description | Purpose. The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP+) and reduced haloperidol pyridinium (RHP+). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural analogues of N-methyl-4-phenylpyridinium (MPP+), a well-known neurotoxin. RHP+ can be oxidized to HP+ by CYP1A1. In the current study, the oxidation of RHP+ to HP+ was investigated using human placenta microsomal preparations which contain relatively high levels of CYP1A1. Methods. Cytochrome P450 isoenzymes responsible for the metabolism of RHP+ were characterized in vitro using human placenta microsomal preparations from smokers and non-smokers. Results. A comparison of the metabolic activities between smokers and non-smokers suggests that smokers had higher activities for the oxidation of RHP+. A selective antibody against CYP1A1 was a partial inhibitor of RHP+ oxidase in placenta from smokers but had no effect in placenta from non-smokers. Furafylline and ketokonazole were shown to be stronger inhibitors of the oxidation of RHP+ to HP+ in liver than in placenta. This seems to indicate important contributions of CYP1A1 and CYP3A7 as compared to CYP1A2 and CYP3A4, respectively, because furafylline and ketokonazole are stronger inhibitors of CYP1A2 and CYP3A4 than CYP1A1 and CYP3A7, respectively. Interestingly, α-naphathoflavone enhanced the metabolic activity in liver microsomes due to its activator effect on CYP3A4. On the other hand, α-naphathoflavone partially inhibited the activity in placenta microsomes, indicating a role played by CYP1A1 or CYP1A2 in the oxidation of RHP+ in placenta. Conclusions. These data indicate that CYP1A1 plays an important role in the oxidation of RHP+ to HP+ in placenta from smokers. CYP3A7 and CYP3A4 could also play important roles in the metabolism of RHP+ in placenta microsomes.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. |
| first_indexed | 2024-03-12T19:39:59Z |
| format | Article |
| id | doaj.art-04d308c175184f91b817e41424acb9ac |
| institution | Directory Open Access Journal |
| issn | 1482-1826 |
| language | English |
| last_indexed | 2024-03-12T19:39:59Z |
| publishDate | 2012-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Journal of Pharmacy & Pharmaceutical Sciences |
| spelling | doaj.art-04d308c175184f91b817e41424acb9ac2023-08-02T03:52:10ZengFrontiers Media S.A.Journal of Pharmacy & Pharmaceutical Sciences1482-18262012-10-0115410.18433/J31W20In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of SmokingJim Fang0Jiuxue Song1College of Pharmacy and Nutrition University of Saskatchewan SaskatoonCollege of Pharmacy and Nutrition University of Saskatchewan SaskatoonPurpose. The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP+) and reduced haloperidol pyridinium (RHP+). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural analogues of N-methyl-4-phenylpyridinium (MPP+), a well-known neurotoxin. RHP+ can be oxidized to HP+ by CYP1A1. In the current study, the oxidation of RHP+ to HP+ was investigated using human placenta microsomal preparations which contain relatively high levels of CYP1A1. Methods. Cytochrome P450 isoenzymes responsible for the metabolism of RHP+ were characterized in vitro using human placenta microsomal preparations from smokers and non-smokers. Results. A comparison of the metabolic activities between smokers and non-smokers suggests that smokers had higher activities for the oxidation of RHP+. A selective antibody against CYP1A1 was a partial inhibitor of RHP+ oxidase in placenta from smokers but had no effect in placenta from non-smokers. Furafylline and ketokonazole were shown to be stronger inhibitors of the oxidation of RHP+ to HP+ in liver than in placenta. This seems to indicate important contributions of CYP1A1 and CYP3A7 as compared to CYP1A2 and CYP3A4, respectively, because furafylline and ketokonazole are stronger inhibitors of CYP1A2 and CYP3A4 than CYP1A1 and CYP3A7, respectively. Interestingly, α-naphathoflavone enhanced the metabolic activity in liver microsomes due to its activator effect on CYP3A4. On the other hand, α-naphathoflavone partially inhibited the activity in placenta microsomes, indicating a role played by CYP1A1 or CYP1A2 in the oxidation of RHP+ in placenta. Conclusions. These data indicate that CYP1A1 plays an important role in the oxidation of RHP+ to HP+ in placenta from smokers. CYP3A7 and CYP3A4 could also play important roles in the metabolism of RHP+ in placenta microsomes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/16594 |
| spellingShingle | Jim Fang Jiuxue Song In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking Journal of Pharmacy & Pharmaceutical Sciences |
| title | In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking |
| title_full | In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking |
| title_fullStr | In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking |
| title_full_unstemmed | In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking |
| title_short | In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking |
| title_sort | in vitro characterization of the oxidation of a pyridinium metabolite of haloperidol by human placenta the effect of smoking |
| url | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/16594 |
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