Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells
Published by Elsevier B.V..
Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 μM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 μM for CQ and 16.3 μM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:393 |
|---|---|
| Enthalten in: |
Toxicology letters - 393(2024) vom: 15. März, Seite 84-95 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Xilin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
4QWG6N8QKH |
|---|
| Anmerkungen: |
Date Completed 13.03.2024 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.toxlet.2024.01.012 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36819101X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36819101X | ||
| 003 | DE-627 | ||
| 005 | 20240313234224.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240209s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.toxlet.2024.01.012 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1326.xml |
| 035 | |a (DE-627)NLM36819101X | ||
| 035 | |a (NLM)38311193 | ||
| 035 | |a (PII)S0378-4274(24)00021-3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Xilin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 13.03.2024 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier B.V. | ||
| 520 | |a Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 μM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 μM for CQ and 16.3 μM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Chloroquine | |
| 650 | 4 | |a Chromosomal damage | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a Hydroxychloroquine | |
| 650 | 4 | |a TK6 cells | |
| 650 | 7 | |a Hydroxychloroquine |2 NLM | |
| 650 | 7 | |a 4QWG6N8QKH |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a Chloroquine |2 NLM | |
| 650 | 7 | |a 886U3H6UFF |2 NLM | |
| 700 | 1 | |a Le, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yuxi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Si |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Manjanatha, Mugimane G |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Nan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Toxicology letters |d 1980 |g 393(2024) vom: 15. März, Seite 84-95 |w (DE-627)NLM012622583 |x 1879-3169 |7 nnns |
| 773 | 1 | 8 | |g volume:393 |g year:2024 |g day:15 |g month:03 |g pages:84-95 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.toxlet.2024.01.012 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 393 |j 2024 |b 15 |c 03 |h 84-95 | ||