Exogenous Iron Increases Fasciocidal Activity and Hepatocellular Toxicity of the Synthetic Endoperoxides OZ78 and MT04.

Brecht Brecht,Trapani Trapani,Bouitbir Bouitbir,Keiser Keiser,Krähenbühl Krähenbühl,Kirchhofer Kirchhofer

doi:10.3390/ijms20194880

Abstract

The synthetic peroxides OZ78 and MT04 recently emerged as fasciocidal drug candidates. However, the effect of iron on fasciocidal activity and hepatocellular toxicity of these compounds is unknown. We investigated the in vitro fasciocidal activity and hepatocellular toxicity of OZ78 and MT04 in absence and presence of Fe(II)chloride and hemin, and conducted a toxicological study in mice. Studies were performed in comparison with the antimalarial artesunate (AS), a semisynthetic peroxide. Fasciocidal effects of OZ78 and MT04 were confirmed and enhanced by Fe2+ or hemin. In HepG2 cells, AS reduced cellular ATP and impaired membrane integrity concentration-dependently. In comparison, OZ78 or MT04 were not toxic at 100 µM and reduced the cellular ATP by 13% and 19%, respectively, but were not membrane-toxic at 500 µM. The addition of Fe2+ or hemin increased the toxicity of OZ78 and MT04 significantly. AS inhibited complex I, II, and IV of the mitochondrial electron transport chain, and MT04 impaired complex I and II, whereas OZ78 was not toxic. All three compounds increased cellular reactive oxygen species (ROS) concentration-dependently, with a further increase by Fe2+ or hemin. Mice treated orally with up to 800 mg OZ78, or MT04 showed no relevant hepatotoxicity. In conclusion, we confirmed fasciocidal activity of OZ78 and MT04, which was increased by Fe2+ or hemin. OZ78 and MT04 were toxic to HepG2 cells, which was explained by mitochondrial damage associated with ROS generation in the presence of iron. No relevant hepatotoxicity was observed in mice in vivo, possibly due to limited exposure and/or high antioxidative hepatic capacity.

Highlights

Fasciola hepatica (F. hepatica) is a food-borne trematode, which infects 2 to 17 million people worldwide
Worms incubated with MT04 alone were not affected after 24 h
We focused on potential hepatic adverse effects of AS, OZ78, and MT04 in mice

Summary

Introduction

Fasciola hepatica (F. hepatica) is a food-borne trematode, which infects 2 to 17 million people worldwide. The parasite settles in the liver, bile ducts, and the gallbladder of the host, causing fascioliasis. A global burden of about 1.7 million DALYs (disability-adjusted life years) has been. 2019, 20, 4880; doi:10.3390/ijms20194880 www.mdpi.com/journal/ijms opens the endoperoxide group of these molecules, eventually leading to the formation of C-centered radicals that can react with different cell constituents, such as heme, phospholipids, proteins, and DNA [14,17,19]. It has been proposed that heme produced by the degradation of hemoglobin by malaria parasites is responsible for the activation and for the pharmacological activity

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