Toxicity Screening of Novel Myeloperoxidase Inhibitors Using Zebrafish Model

Abstract

Myeloperoxidase (MPO) is a heme-containing enzyme, which is stored and released by neutrophils and monocytes. MPO catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride ion. Hypochlorous acid (HOCl) is a potent oxidizer and microbicidal chemical. In previous studies, we found that compounds that contain hydrazine moieties were effective inhibitors of MPO and, thereby, had the ability to decrease the production of HOCL. In our study, we tested hydrazine derivatives on zebrafish embryos to observe the toxicity effect in the circulatory system of the embryos including heart rate changes and cardiac edema. Furthermore, in situ hybridizations of liver cells using liver probe was applying to determine the safety of these compounds on the liver of the embryos. We found that isoniazid, 2-aminobenzoic acid hydrazide (2-ABAH), 4-aminobenzoic acid hydrazide (4-ABAH), 3-(dimethylamino) benzoic acid hydrazide (3-DMABAH), and 4-flurobenzoic acid hydrazide (4-FBAH) have little or no effect on heart rate. While sodium azide (NaN3), 4-nitrobenzoic acid hydrazide (4-NBAH), and 4-(trifluromethyl) benzoic acid hydrazide (4-TFMBAH) caused severe edema and lowered heart rates as well as the delay of the liver development. The toxic effect of benzoic acid hydrazide (BAH) appeared only in a very high concentration. However, more experiments on mammalian model organisms will be needed to support the toxicity results.