No abstract

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.

Uric acid (UA) is an end product of purine metabolism by the enzyme xanthine oxidase (XOD). Hyperuricemia is characterized by the accumulation of serum UA and is an important risk factor for gout and many chronic disorders. XOD inhibitors or uricase (catalyzes UA to the more soluble end product) can prevent these chronic diseases. However, currently available hypouricemic agents induce severe side effects. Therefore, we developed new microbial fermented extracts (MFEs) with substantial XOD inhibition activity from Lactobacillus (MFE-21) and Acetobacter (MFE-25), and MFE-120 with high uricase activity from Aspergillus. The urate-lowering effects and safety of these MFEs were evaluated. Our results showed that MFE-25 exerts superior urate-lowering effects in the therapeutic model. In the preventive model, both MFE-120 and MFE-25 significantly reduced UA. The results of the safety study showed that no organ toxicity and no treatment-related adverse effects were observed in mice treated with high doses of MFEs. Taken together, the results showed the effectiveness of MFEs in reducing hyperuricemia without systemic toxicity in mice at high doses, suggesting that they are safe for use in the treatment and prevention of hyperuricemia.

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.

No abstract