Altered cellular metabolism of HepG2 cells caused by microcystin-LR

• Published in: Environmental pollution (1987) 2017-06, Vol.225, p.610-619
• Main Authors: Ma, Junguo, Feng, Yiyi, Jiang, Siyu, Li, Xiaoyu
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Ascorbic Acid; Caspase 3 - metabolism; Cell Survival - drug effects; Drug resistance gene; Hep G2 Cells; HepG2; Humans; Lipid Peroxidation; Membrane Potential, Mitochondrial; Metabolism-associated enzyme; Microcystin-LR; Microcystins - toxicity; OATPs; Toxicity Tests
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2017.03.029

This study aimed to evaluate the possible effects of microcystin-LR (MC-LR) exposure on the metabolism and drug resistance of human hepatocellular carcinoma (HepG2) cells. For this purpose, we first conducted an experiment to make sure that MC-LR could penetrate the HepG2 cell membrane effectively. The transcriptional levels of phase I (such as CYP2E1, CYP3A4, and CYP26B1) and phase II (such as EPHX1, SULTs, and GSTM) enzymes and export pump genes (such as MRP1 and MDR1) were altered by MC-LR-exposure for 24 h, indicating that MC-LR treatment may destabilize the metabolism of HepG2 cells. Further research showed that the CYP inducers omeprazole, ethanol, and rifampicin inhibited cell viability, in particular, ethanol, a CYP2E1 inducer, induced ROS generation, lipid peroxidation, and apoptosis in HepG2 cells treated with MC-LR. The CYP2E1 inhibitor chlormethiazole inhibited ROS generation, mitochondrial membrane potential loss, caspase-3 activity, and cytotoxicity caused by MC-LR. Meanwhile, the results also showed that co-incubation with the ROS scavenger l-ascorbic acid and MC-LR decreased ROS levels and effectively prevented apoptosis. These findings provide an interesting mechanistic explanation of cellular metabolism associated with MC-LR, i.e., MC-LR-exposure exerted toxicity on HepG2 cells and induced apoptosis of HepG2 cells via promoting CYP2E1 expression and inducing excessive ROS in HepG2 cells. [Display omitted] •MC-LR could penetrate HepG2 cell membrane effectively.•MC-LR-exposure disturb the metabolic destabilization of HepG2 cells.•CYP2E1 plays an important role in cellular metabolism of HepG2 cells caused by MC-LR. The linkage between CYP2E1-dependent oxidative stress and mitochondrial injury contributes to the toxic action of MC-LR on HepG2 cells.