Polychlorinated Biphenyls And Their Metabolites Inhibit The Ability And Mechanism Of Action Of Glutathione S-transferase Enzyme

As typical persistent organic pollutants, PCBs are a group of chlorinated aromatic compounds, and have difficult degradable characteristics, biological toxicity, bioaccumulation, long-range transport characteristics. PCBs are one of the priority control in12categories of persistent organic pollutants in the Stockholm Convention.PCBs have a high retention in the environment, but they can slowly transformed into other metabolites in vivo. PCBs are absorbed into the body through various way, and they will be occurred a series of chemical changes and generate decomposition products or derivatives, namely biotransformation. The two major enzymes involved in this process, cytochrome P450enzymes and glutathione S-transferase enzyme. The study of CYP450enzymes is relatively penetrating;further research is needed for the GSTs.GSTs are a group of isoenzyme family with a variety of physiological functions, and are the body’s most important two-phase metabolic enzymes. Thus, GSTs are considered an effective antidote, and plays a vital role in protecting the body from the environmental poison damage. Reduced its activity or suppressed will bring a range of adverse effects.PCBs researches mainly focus on parent PCBs. However, some studies suggested that PCB metabolites may be more interesting than the parent due to their high reactivity. As a key metabolic enzyme, glutathione S-transferase isoenzymes (GSTs) are responsible for detoxifying by catalyzing the conjugation reaction of xenobiotics with GSH. The inhibition of GSTs activity indicated the reduction of detoxification ability. Therefore, it is quite possible that PCB and PCB metabolites could inhibit GSTs activity to some extent. However, there is no direct evidence of PCBs and their metabolites inhibiting GSTs activity.In this paper, the inhibition of chicken liver GSTs by parent PCBs and their different level metabolites were investigated. We examined the dose-dependent inhibition of GSTs activities in vitro, and the inhibitory efficiency was declining in the order of GSH-conjugate> mono-hydroxyl≈quinone≈hydroquinone> parent PCB. Structure-inhibitory activity relationships study indicated that the GSH moiety increased the inhibitory activity of glutathionylated quinone analogues. Also, with the chlorine degree increasing on the quinone ring, the inhibitory activity increased dramatically. However, there is no significant linear relationship was found with chlorine pattern change on the phenyl ring. The reversible and irreversible nature of PCB metabolites inhibit GSTs were also discussed. PCB mono-hydroxyl, hydroquinones and quinones were irreversible inhibition towards GSTs, which suggested the covalent binding with cysteine residues on the active site of GSTs. PCB glutathionyl conjugate showed reversible GSTs inhibition manner, imply non-covalent binding. Furthermore, reactive oxygen species have no significant affection on GSTs inhibition. These findings suggest that the inhibition of GSTs activity might be associated with PCBs toxic effect.