Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons

Abstract

1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.

Effect of astragaloside on diaphragm cell apoptosis in chronic obstructive pulmonary disease

“…As a typical traditional Chinese medicine, AST has been widely used for anti-inflammatory treatment (Hsieh, Liu, Chen, Huang, & Wu, 2020;Xie et al, 2020;Zhang et al, 2020). Our study indicated (Ijiri et al, 2018). Caspase-3 is one of the major executioners of apoptosis (Langford, McGee, Ta, Redens, & Texada, 2011).…”

“…Multiple signal transmitting pathways act collectively with caspases to induce apoptosis. Particularly, caspase‐9 is an initiator caspase participating in mitochondrial apoptosis and other apoptosis pathways (Ijiri et al., 2018). Caspase‐3 is one of the major executioners of apoptosis (Langford, McGee, Ta, Redens, & Texada, 2011).…”

Expression levels of caspase‐3 and gasdermin E and their involvement in the occurrence and prognosis of lung cancer

“…The activation of these caspases is a biochemical marker of apoptosis. 26 Apoptosis has been defined as a type of programmed cell death, 27 which proceeds through two classical signal transduction pathways: the external and internal pathways. 28 The external pathway is mediated by caspase‐8, whereas the internal pathway is triggered by caspase‐9.…”

Expression levels of caspase-3 and gasdermin E and their involvement in the occurrence and prognosis of lung cancer

“…The activation of these caspases is a biochemical marker of apoptosis [25]. Apoptosis has been de ned as a type of programmed cell death [26], which proceeds through two classical signal transduction pathways: the external and internal pathways [27]. The external pathway is mediated by caspase-8, whereas the internal pathway is triggered by caspase-9.…”