Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0–72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, RTTCC was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O2). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.
Highlights
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally due to its high transmissibility and infectivity, resulting in an unprecedented global public health challenge (Rothe et al, 2020; Sohrabi et al, 2020)
Human lung carcinomatous cell lines A549 cells were maintained in McCoy’s 5A Media (Modified with Tricine), hepatocellular carcinoma cells Hep3B and human embryonic kidney cell line HEK293 cells were maintained in Minimum Essential Medium (MEM Eagles with Earle’s Balanced Salts) (MEM-EBSS), and rat small intestinal epithelial cell line IEC-6 cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 0.01 mg/ml bovine insulin; these cell lines were acquired from National Infrastructure of Cell Line Resource
The pictures reflecting the effects of CQ and HCQ on cell morphology and confluences are shown in Supplementary Figure S2
Summary
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally due to its high transmissibility and infectivity, resulting in an unprecedented global public health challenge (Rothe et al, 2020; Sohrabi et al, 2020). Treatments are urgently needed to cure respiratory failure and deaths caused by coronavirus disease 2019 (covid-19; Lu, 2020). Several in vitro studies have reported the activity by chloroquine (CQ) and hydroxychloroquine (HCQ) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Colson et al, 2020; Liu et al, 2020; Wang et al, 2020; Yao et al, 2020). Both CQ and HCQ have received worldwide attention as a choice for covid-19 in a short time. The safety and effectiveness of CQ and HCQ in the treatment of new coronavirus pneumonia are still controversial, which need further study
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