1, 2-Dichloropropane generates phosphorylated histone H2AX via cytochrome P450 2E1-mediated metabolism. (15th April 2017)

• Record Type: Journal Article
• Authors: Toyooka, Tatsushi; Yanagiba, Yukie; Suda, Megumi; Ibuki, Yuko; Wang, Rui-Sheng
• Is Part Of: Toxicology letters. Volume 272(2017)
• Page Start: 60
• Page End: 67
• Publication Date: 2017-04-15
• Subjects: 1, 2-DCP 1, 2-dichloropropane -- 4MP 4-methylpyrazole -- ABT 1-aminobenzotriazole -- BSA bovine serum albumin -- BSFGE biased sinusoidal field gel -- CYP2E1 electrophoresis -- DAPI 4′, 6-diamidino-2-phenylindole -- DCFH-DA 6-carboxy-2, 7′-diclorodihydrofluorescein diacetate, di(acetoxy ester) -- DSBs double-strand breaks -- DSF disulfiram -- FCM flow cytometer -- H2O2 hydrogen peroxide -- NAC N-acetylcysteine -- PI propidium iodide -- ROS reactive oxygen species -- SSBs single-strand breaks -- γ-H2AX phosphorylated histone H2AX; 1, 2-Dichloropropane -- Genotoxicity -- Phosphorylated histone H2AX -- Cytochrome P450 2E1 -- Reactive oxygen species; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2017.03.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: 1, 2-DCP generated γ-H2AX in WRL-68 and MMNK-1 cell lines and inhalationally exposed livers of mice. 1, 2-DCP-generated γ-H2AX was attenuated by CYP2E1 inhibitors. ROS produced via the CYP2E1 metabolic process of 1, 2-DCP was a major causal factor for γ-H2AX generation by 1, 2-DCP. Abstract: 1, 2-Dichloropropane (1, 2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1, 2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1, 2-DCP. In this study, we examined the genotoxicity of 1, 2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1, 2-DCP showed dose- (1–10 mM: 4 h) and time-dependent (1–24 h: 5 mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, γ-H2AX generation was observed in the livers of mice inhalationally exposed to 1, 2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, we found that γ-H2AX generation by 1, 2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1, 2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. These results suggested that ROS produced via the cytochrome P450 2E1 metabolic process of 1, 2-DCP was a major causal factor for γ-H2AX generation by treatment with 1, 2-DCP.