Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes
Abstract Background The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P450-mediated pathways. Human erythrocytes generally are not considered a sign...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-01-01
|
| Series: | Malaria Journal |
| Online Access: | http://link.springer.com/article/10.1186/s12936-019-2658-5 |
| _version_ | 1818912945903501312 |
|---|---|
| author | Pius S. Fasinu N. P. Dhammika Nanayakkara Yan-Hong Wang Narayan D. Chaurasiya H. M. Bandara Herath James D. McChesney Bharathi Avula Ikhlas Khan Babu L. Tekwani Larry A. Walker |
| author_facet | Pius S. Fasinu N. P. Dhammika Nanayakkara Yan-Hong Wang Narayan D. Chaurasiya H. M. Bandara Herath James D. McChesney Bharathi Avula Ikhlas Khan Babu L. Tekwani Larry A. Walker |
| author_sort | Pius S. Fasinu |
| collection | DOAJ |
| description | Abstract Background The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P450-mediated pathways. Human erythrocytes generally are not considered a significant contributor to drug biotransformation. As erythrocytes are the target of primaquine toxicity, the ability of erythrocytes to mediate the formation of reactive oxidative primaquine metabolites in the absence of hepatic enzymes, was evaluated. Methods Primaquine and its enantiomers were incubated separately with human red blood cells and haemoglobin. Post-incubation analysis was performed with UPLC–MS/MS to identify products of biotransformation. Results The major metabolite detected was identified as primaquine-5,6-orthoquinone, reflecting the pathway yielding putative active and haematotoxic metabolites of primaquine, which was formed by oxidative demethylation of 5-hydroxyprimaquine. Incubation of primaquine with haemoglobin in a cell-free system yielded similar results. It appears that the observed biotransformation is due to non-enzymatic processes, perhaps due to reactive oxygen species (ROS) present in erythrocytes or in the haemoglobin incubates. Conclusion This study presents new evidence that primaquine-5,6-orthoquinone, the metabolite of primaquine reflecting the oxidative biotransformation pathway, is generated in erythrocytes, probably by non-enzymatic means, and may not require transport from the liver or other tissues. |
| first_indexed | 2024-12-19T23:22:40Z |
| format | Article |
| id | doaj.art-bef9c2cb44b441a495645be8bf521194 |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-12-19T23:22:40Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-bef9c2cb44b441a495645be8bf5211942022-12-21T20:01:56ZengBMCMalaria Journal1475-28752019-01-011811810.1186/s12936-019-2658-5Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytesPius S. Fasinu0N. P. Dhammika Nanayakkara1Yan-Hong Wang2Narayan D. Chaurasiya3H. M. Bandara Herath4James D. McChesney5Bharathi Avula6Ikhlas Khan7Babu L. Tekwani8Larry A. Walker9The National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiIronstone Separations, Inc.The National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiThe National Center for Natural Products Research, The University of MississippiAbstract Background The activity and haemolytic toxicity associated with primaquine has been linked to its reactive metabolites. The reactive metabolites are thought to be primarily formed through the action of cytochrome P450-mediated pathways. Human erythrocytes generally are not considered a significant contributor to drug biotransformation. As erythrocytes are the target of primaquine toxicity, the ability of erythrocytes to mediate the formation of reactive oxidative primaquine metabolites in the absence of hepatic enzymes, was evaluated. Methods Primaquine and its enantiomers were incubated separately with human red blood cells and haemoglobin. Post-incubation analysis was performed with UPLC–MS/MS to identify products of biotransformation. Results The major metabolite detected was identified as primaquine-5,6-orthoquinone, reflecting the pathway yielding putative active and haematotoxic metabolites of primaquine, which was formed by oxidative demethylation of 5-hydroxyprimaquine. Incubation of primaquine with haemoglobin in a cell-free system yielded similar results. It appears that the observed biotransformation is due to non-enzymatic processes, perhaps due to reactive oxygen species (ROS) present in erythrocytes or in the haemoglobin incubates. Conclusion This study presents new evidence that primaquine-5,6-orthoquinone, the metabolite of primaquine reflecting the oxidative biotransformation pathway, is generated in erythrocytes, probably by non-enzymatic means, and may not require transport from the liver or other tissues.http://link.springer.com/article/10.1186/s12936-019-2658-5 |
| spellingShingle | Pius S. Fasinu N. P. Dhammika Nanayakkara Yan-Hong Wang Narayan D. Chaurasiya H. M. Bandara Herath James D. McChesney Bharathi Avula Ikhlas Khan Babu L. Tekwani Larry A. Walker Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes Malaria Journal |
| title | Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| title_full | Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| title_fullStr | Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| title_full_unstemmed | Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| title_short | Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| title_sort | formation primaquine 5 6 orthoquinone the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes |
| url | http://link.springer.com/article/10.1186/s12936-019-2658-5 |
| work_keys_str_mv | AT piussfasinu formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT npdhammikananayakkara formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT yanhongwang formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT narayandchaurasiya formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT hmbandaraherath formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT jamesdmcchesney formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT bharathiavula formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT ikhlaskhan formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT babultekwani formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes AT larryawalker formationprimaquine56orthoquinonetheputativeactiveandtoxicmetaboliteofprimaquineviadirectoxidationinhumanerythrocytes |