Benzene metabolite 1,2,4-benzenetriol induces halogenated DNA and tyrosines representing halogenative stress in the HL-60 human myeloid cell line

Although benzene is known to be myelotoxic and to cause myeloid leukaemia in humans, the mechanism has not been elucidated. In the present study, the authors focused on 1,2,4-benzenetriol (BT), a benzene metabolite that generates reactive oxygen species (ROS) by autoxidation, to investigate the toxicity of benzene leading to leukemogenesis. After exposing HL-60 human myeloid cells to BT, the authors investigated the cellular effects, including apoptosis, ROS generation, DNA damage, and protein damage. In addition, they investigated how the cellular effects of BT were modified by hydrogen peroxide (H2O2) scavenger catalase, hypochlorous acid (HOCl) scavenger methionine, and 4-aminobenzoic acid hydrazide (ABAH), a myeloperoxidase (MPO)-specific inhibitor. BT increased the levels of apoptosis and ROS, including superoxide (O2*-), H2O2, HOCl, and the hydroxyl radical (*OH). Catalase, ABAH, and methionine each inhibited the increased apoptosis caused by BT, and catalase and ABAH inhibited increases in HOCl and *OH. Although BT exposure increased halogenated DNA, this increase was inhibited by catalase, methionine, and ABAH. BT exposure also increased the amount of halogenated tyrosines; however, it did not increase 8-oxo-deoxyguanosine. The authors concluded that BT increases H2O2 intracellularly; this H2O2 is metabolised to HOCl by MPO, and this HOCl results in possibly cytotoxic binding of chlorine to DNA. Because myeloid cells copiously express MPO and because halogenated DNA may induce both genetic and epigenetic changes that contribute to carcinogenesis, halogenative stress may account for benzene-induced bone marrow disorders and myeloid leukaemia.

Authors: Nishikawa, Takuro; Miyahara, Emiko; Horiuchi, Masahisa; Izumo, Kimiko; Okamoto, Yasuhiro; Kawai, Yoshichika; Kawano, Yoshifumi; Takeuchi, Toru ;Full Source: Environmental Health Perspectives 2012, 120(1), 62-67 (Eng) ;