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Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

Science China(Life Sciences) 2024年第2期67卷 301-319页

作者： Xiaoli Tang Hong Liu Rongjia Rao Yafei Huang Mengqi Dong Miaomiao Xu Shanshan Feng Xun Shi Li Wang Zengwu Wang Bingying Zhou State Key Laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100037China Department of Epidemiology Cardiovascular Institute and Fuwai HospitalChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100037China Shenzhen Key Laboratory of Cardiovascular Disease Fuwai Hospital Chinese Academy of Medical SciencesShenzhenShenzhen 518020China

mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’***,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening *** accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h ***,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT *** a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced *** study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.

关键词： remdesivir mitochondrial toxicity cardiotoxicity human primary cardiomyocytes high-throughput screening

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mitochondrial toxicity and new China goals for TT21C/Adverse Outcome Pathways

Mitochondrial toxicity and new China goals for TT21C/Adverse...

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中国毒理学会第六届全国毒理学大会

作者： PENG Shuang-qing GUO Jia-bin YUAN Hai-tao ZHANG Ting-fen HOU Ming-yue ZHAO Jun LI Jin Paul CARMICHAEL Evaluation and Research Centre for Toxicology Institute of Disease Control and PreventionAcademy of Military Medical Sciences Unilever Safety and Environmental Assurance Centre

＜正＞Mitochondria are major sources of cellular energy and reactive oxygen species （ROS）,playing fundamental roles in regulation of cell survival and death under pathological conditions. Numerous chemicals have shown to significantly induce mitochondrial toxicity in targeted organ such as liver and *** identification of mitochondrial toxicity for chemicals is important for avoiding hazard exposure in human or environment. However,due to the complexity of mitochondrial toxicity which may involve multiple mechanisms,the assessment of mitochondrial toxicity based on animal test is unsatisfactory. The release of toxicity Testing in the Twenty-First Century:Vision and A Strategy by the US National Research Council brings new perspectives to the strategy and methods on the assessment of chemical-induced mitochondrial *** development of toxicity testing of mitochondrial toxicity is also transforming expensive and lengthy traditional in vivo animal tests to in vitro high-throughput alternative methods with quantitative parameters analysis and mechanistic exploration. Recently,many in vitro alternative methods have been established for accessing chemical-induced mitochondrial toxicity,such as high content screening,mechanism-based toxicity testing（eg, mitochondrial membrane potential,ATP production, oxygen consumption rate,oxidative phosphorylation, and mitochondrial superoxide generation）. In particular,adverse outcome pathway （AOP）for mitochondrial toxicity is highlighted to get a better mechanistic understanding and in vitro to in vivo *** AOP integrates from chemical characterization to molecular initiating event（MIE）and population response.A significant effort has been made by Chinese scientists to establish and develop Chinese TT21C/*** on previous studies in toxicological alternatives,many new projects have been carried out using TT21C strategies to access toxicitv of various chemicals.

关键词： mitochondrial toxicity toxicity testing risk assessment

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Hepatotoxicity reports in the FDA adverse event reporting system database:A comparison of drugs that cause injury via mitochondrial or other mechanisms

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3857-3868页

作者： Payal Rana Michael D.Aleo Xuerong Wen Stephen Kogut Drug Safety Research&Development PfizerGrotonCT 06340USA University of Rhode Island College of PharmacyKingstonRI 02881USA

Drug-induced liver injury(DILI) is a leading reason for preclinical safety attrition and postmarket drug ***-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI,especially in idiosyncratic liver *** study examined liver injury reports submitted to the Food and Drug Administration(FDA) Adverse Event Reporting System(FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of *** frequency of hepatotoxicity was determined at a group level and individual drug level.A reporting odds ratio(ROR) was calculated as the measure of *** the two DILI groups,reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43(95% CI 1.42-1.45;P mitochondrial mechanisms of ***,antiviral,analgesic,antibiotic,and antimycobacterial drugs were the top five drug classes with the highest ROR *** the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms,the top four drugs(ROR values> 18:benzbromarone,troglitazone,isoniazid,rifampin) were associated with mitochondrial mechanisms of *** major demographic influence for DILI risk was also *** was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1±18.33(SD)] compared to non-mitochondrial mechanisms [48±19.53(SD)](P mitochondrial mechanisms of *** logistic regression analysis showed that reports of liver injury were 2.2(odds ratio:2.2,95% CI 2.12-2.26) times more likely to be associated with older patient age,as compared with reports involving patients less than 65 years of *** to males,female patients were 37% less likely(odds ratio:0.63,95% CI

关键词： mitochondrial toxicity FAERS database Adverse event reporting Drug-induced liver injury Hepatotoxicity

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Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection

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Journal of Clinical and Translational Hepatology 2016年第4期4卷 328-335页

作者： Jose D.Debes Paul R.Bohjanen Andre Boonstra Department of Medicine Division of Infectious Disease and International Medicine University of MinnesotaMinneapolis MN USA Department of Gastroenterology and Hepatology Erasmus MC Rotterdam The Netherlands

With the introduction of antiretroviral therapy (ART),a dramatic reduction in HIV-related morbidity and mortality has been ***,it is now becoming increasingly clear that liver-related complications,particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself,are of serious concern to HIV *** pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication,and bacterial translocation lead to chronic immune activation and inflammation,which ART is unable to fully suppress,promoting production of fibrinogenic mediators and *** addition,mitochondrial toxicity,triggered by both ART and HIV,contributes to intrahepatic damage,which is even more severe in patients co-infected with viral *** recent years,new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained,and these are detailed and discussed in this review.

关键词： HIV Liver fibrosis mitochondrial toxicity Bacterial translocation

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