Toxicological effects of some antiparasitic drugs on equine liver glutathione S-Transferase enzyme activity
Introduction
Glutathione S-transferase (GSTs: E.C.2.5.1.18) as a multifunctional enzyme catalyzes the first step formation of mercapturic acid that occurs as a final product in the detoxification metabolic process [1,2]. The GSTs enzyme is present in the liver of mammals such as humans, rats, and mice [3,4]. Additionally, GSTs presents in plants, fungi, insects, and bacteria [5]. Mitochondrial, cytosolic and microsomal enzymes are GSTs derivatives, and these enzymes metabolize various electrophilic based chemicals by the conjugation of reduced glutathione [6,7]. The formation of mercapturic acid occurs in the first phase of the conjugation reaction in which the organism can eliminate and inactivate the harmful endobiotic and xenobiotics [8,9]. Additionally, GSTs also play an important role in the detoxification of xenobiotics reaction in prokaryotes [10,11]. The GSTs enzyme has been found to be associated with an increase in bacterial resistance to some antibiotics such as rifampicin and tetracycline [12,13].
Various new benzimidazoles derivatives have been developed, which used for the enhancing of antiparasitic activity and for the change of pharmacokinetic properties [[14], [15], [16]]. The drugs in the benzimidazole class are widely used in the prevention and treatment of parasitic diseases in veterinary medicine [[16], [17], [18], [19]].
Ricobendazole is a compound of the benzimidazole drug class, and also called albendazole sulfoxide. Ricobendazole is a broad spectrum compound that is effectively used against lungworms and nematodes. In some Latin American countries, such as Argentina, an aqueous solution of Ricobendazole is being prepared and used in cattle subcutaneous injections by veterans and farmers [20].
Tiabendazole is a post-harvest pesticide used to control diseases caused by fungi, it may cause cell death by apoptosis of hepatocyte and may cause human death by damaging the liver [21].
Albendazole is used in a variety of experimental and clinical chemotherapy trials of various intestinal and systematic parasitoses. Albendazole is a broad-spectrum anthelmintic approved for human use for the first time in 1982. It is generally used against systematic parasites, only used for intestinal absorption due to its low aqueous solubility. So, long treatments and high doses are used at appropriate concentrations [22,23].
Oxfendazole contains methylcarbamate, and it is a benzimidazole compound [24]. Oxfendazole is a highly effective drug for zoonotic diseases such as fasciolosis, echinococcosis, and cysticercosis. It is also very effective in the treatment of pig cysticercosis [25,26]. Also, oxfendazole is an effective drug that is cheap, has no side effects and is suitable for human use after treatment [27]. Some studies have reported that degradation of some antibiotics (sulfathiazole, ampicillin) has been found in microorganisms receiving GSTs enzyme under specified conditions [28,29]. Normally, the binding of inhibitors to active sites in the GSTs enzyme results in slowing or stopping enzyme activity [30,31]. There are many drugs that can inhibit the GSTs enzyme, and herbicides and pesticides also have an inhibitory effect on the GSTs enzyme. The detection of drugs in biochemical studies as an inhibitor is crucial [14,32]. Our most important goal in this study is to emphasize the use of antiparasitics which can inhibit this enzyme which has a vital role in metabolism. Herein, we investigated in vitro the inhibitory effects of benzimidazole drugs such as ricobendazole, thiabendazole, albendazole and oxfendazole compounds on GSTs enzyme activity, using the 1-chloro-2,4-dinitrobenzene (CDNB) solution as a substrate for GSTs enzyme, respectively Fig. 1.
Section snippets
Chemicals
GSTs enzyme obtained from the equine liver (Sigma-Aldrich G6511, USA) was used for inhibition study. Ricobendazole (RBZ), thiabendazole (TBZ), albendazole (ALBA), oxfendazole (OFZ), glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB) were purchased from Sigma Aldrich. All glassware used in the experiment were cleaned with purified water.
Results
In this paper, the inhibitory effect of RBZ, TBZ, ALBA, OFZ drugs on GSTs enzyme activity was tested. As detailed below, these benzimidazoles derivatives were investigated for their inhibition properties against GSTs enzymes, and the results showed that these drugs have an impressive effect on the GSTs inhibition. The chemical structures of some benzimidazoles derivatives compounds are shown in Fig. 1. Also, these enzyme inhibiting results of benzimidazoles derivatives compounds are seen in
Discussion
Benzimidazoles (BZMs), a group of heterocyclic compounds, have a fused aromatic imidazole [36]. Benzene ring in the imidazole compound can easily interact with active sites in biological systems via weak interactions such as dipole-ion interactions, hydrophobic interactions, hydrogen bonds, and van der Waals bonds [36,37]. Thanks to this feature, BZMs, and its derivatives can easily be combined with many biological systems. BZMs and its derivatives have been shown to have significant effects on
Conclusion
BZM are antiparasitic drugs and commonly used in various fields such as medicine, agriculture and particularly in veterinary medicine. The experimental results of the tested drugs revealed that BZM derivatives have some significant inhibitory effect on GSTs enzyme activity according to IC50 and Ki values at the micromolar level. These findings are very important because GSTs inhibitors emerge as promising therapy factors for managing the formation of resistance amongst anticancer factors.
Declaration of Competing Interest
The authors declare no conflict of interest.
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