Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays
Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-12-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/12/3272 |
| _version_ | 1797381938426675200 |
|---|---|
| author | Alicia Rosell-Hidalgo Julie Eakins Paul Walker Anthony L. Moore Taravat Ghafourian |
| author_facet | Alicia Rosell-Hidalgo Julie Eakins Paul Walker Anthony L. Moore Taravat Ghafourian |
| author_sort | Alicia Rosell-Hidalgo |
| collection | DOAJ |
| description | Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC<sub>50</sub> = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions. |
| first_indexed | 2024-03-08T20:59:14Z |
| format | Article |
| id | doaj.art-f9fb58084ae242eb97d2b2176627403d |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-08T20:59:14Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-f9fb58084ae242eb97d2b2176627403d2023-12-22T13:55:09ZengMDPI AGBiomedicines2227-90592023-12-011112327210.3390/biomedicines11123272Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro AssaysAlicia Rosell-Hidalgo0Julie Eakins1Paul Walker2Anthony L. Moore3Taravat Ghafourian4Cyprotex Discovery Ltd., No. 24 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UKCyprotex Discovery Ltd., No. 24 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UKCyprotex Discovery Ltd., No. 24 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UKDepartment of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UKDepartment of Pharmaceutical Sciences, Barry & Judy Silverman College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Ft. Lauderdale, FL 33328-2018, USAMitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC<sub>50</sub> = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions.https://www.mdpi.com/2227-9059/11/12/3272mitochondrial toxicityantipsychoticsanticonvulsantsantidepressantsanxiolytic drugsseahorse |
| spellingShingle | Alicia Rosell-Hidalgo Julie Eakins Paul Walker Anthony L. Moore Taravat Ghafourian Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays Biomedicines mitochondrial toxicity antipsychotics anticonvulsants antidepressants anxiolytic drugs seahorse |
| title | Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays |
| title_full | Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays |
| title_fullStr | Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays |
| title_full_unstemmed | Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays |
| title_short | Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays |
| title_sort | risk assessment of psychotropic drugs on mitochondrial function using in vitro assays |
| topic | mitochondrial toxicity antipsychotics anticonvulsants antidepressants anxiolytic drugs seahorse |
| url | https://www.mdpi.com/2227-9059/11/12/3272 |
| work_keys_str_mv | AT aliciarosellhidalgo riskassessmentofpsychotropicdrugsonmitochondrialfunctionusinginvitroassays AT julieeakins riskassessmentofpsychotropicdrugsonmitochondrialfunctionusinginvitroassays AT paulwalker riskassessmentofpsychotropicdrugsonmitochondrialfunctionusinginvitroassays AT anthonylmoore riskassessmentofpsychotropicdrugsonmitochondrialfunctionusinginvitroassays AT taravatghafourian riskassessmentofpsychotropicdrugsonmitochondrialfunctionusinginvitroassays |