Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.
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PMID:The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death. 2458 14

Free radical-triggered tissue damage is believed to play an essential role in a variety of human diseases. Pentachlorophenol (PCP) is applied as a pesticide worldwide in both industries and homes. It is used extensively as a biocide and wood preservative. Tetrachlorohydroquinone (TCHQ) was proved as a major toxic metabolite of PCP, contributing the release of free radicals during PCP metabolism. PCP has been proposed as a tumor promoter; however, only limited knowledge is available regarding the mechanisms of tumor promotion induced by PCP and its metabolite, TCHQ. A growing amount of literature suggests that a link between reactive oxygen species (ROS) and tumor promotion could exist. Herein, we summarize the findings regarding the ROS-triggered signaling pathways involved in the cytotoxicity and tumor promotion effects of PCP and TCHQ. Some of the notable findings demonstrated that TCHQ can induce DNA lesions and glutathione depletion in mammalian cells; meanwhile, oxidative stress and apoptosis/necrosis can be found both in vivo and in vitro. Interestingly, PCP and TCHQ were proved as mild tumor promoters in two-stage tumorigenesis models, in which the possible mechanism could be through ROS generation and changed Bcl-2 gene expression. We also found significant effects of antioxidants in attenuating the oxidative stress, cyto- and genotoxicity, and apoptosis/necrosis induced by PCP and/or TCHQ. In addition, mitogen-activated protein kinase (MAPK) activation is involved in PCP/TCHQ-triggered cytotoxicity, as evidenced by the finding that higher doses of TCHQ could lead to necrosis of freshly isolated splenocytes through the production of a large amount of ROS and sustained ERK activation. These results could explain partly the underlying molecular mechanisms contributing to the tumorigenesis induced by PCP. However, the detailed mechanisms of free radicals in triggering PCP/TCHQ-mediated tumor promotion and toxicity are still not completely resolved and need to be investigated further.
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PMID:ROS-triggered signaling pathways involved in the cytotoxicity and tumor promotion effects of pentachlorophenol and tetrachlorohydroquinone. 2560 7