Metabolism of furazolidone: alternative pathways and modes of toxicity in different cell lines

Abstract

1. The metabolism and cytotoxicity of the antimicrobial nitrofuran drug furazolidone have been studied in Caco-2, HEp-2 and V79 cell lines. Free radical production, metabolite pattern, formation of bound residues, inhibition of cellular replication and protection by the antioxidant glutathione were compared for the three cell lines. 2. All three cell lines produced the same nitro-anion radical with similar kinetics. Little further metabolic breakdown was observed in V79 cells, whereas Caco-2 and HEp-2 cells showed extensive degradation of furazolidone, but with different end patterns. 3. Under hypoxic conditions, the colony-forming ability was extensively impaired in HEp-2 cells whereas the other two cell lines were less affected, suggesting that irreversible damage to DNA occurred prevalently in HEp-2 cells. In V79 cells the absence of oxygen caused a 25-fold increase in the formation of protein-bound residues. 4. Brief exposure to furazolidone caused a 50% loss of endogenous glutathione in Caco-2 cells, but no loss could be detected in V79 and HEp-2 cells. Consistently, when glutathione was depleted by buthionine-[S,R]-sulphoximine (BSO) and diethylmaleate (DEM) treatment, the viability of V79 and HEp-2 cells was minimally affected by furazolidone, whereas that of Caco-2 cells was substantially reduced. 5. It is concluded that the cytotoxicity of furazolidone in these cell lines can be exerted by a number of different mechanisms, possibly related to different metabolic pathways. The cytotoxicity of nitrofuran drugs, therefore, cannot be ascribed to a single toxic intermediate, but in Caco-2 cells furazolidone is extensively metabolized and detoxified by GSH, in V79 is only partially activated and then bound to proteins, whereas in HEp-2, once activated, may react with DNA.

Nitrofuran antibiotics: a review on the application, prohibition and residual analysis

“…Studies suggested that irreversible damage to the DNA of human epithelial cells (HEp-2) as well as hormone disturbances (reflecting endocrine dysfunction) occurred prevalently when cells were exposed to furazolidone (De Angelis et al, 1999;Ahmed et al, 2008). The majority of the information available describes in vivo studies which utilise mouse and rat models for examination of the effects of furazolidone and mainly nitrofurazone or its residue semicarbazide.…”

Curcumin Ameliorates Furazolidone Induced DNA Damage and Apoptosis in Human Hepatocyte L02 Cells via Inhibiting ROS Production and Mitochondrial Pathway

“…FZD showed potential genotoxicity with a dose-dependent manner in a variety of test systems [9,11,[27][28][29][30]. One previous study showed that oral administration of 40 mg/kg of FZD for 10 days could induce marked renal and hepatic toxicity in goat [31].…”

Furazolidone induces the activity of microsomal enzymes that metabolize furazolidone in chickens

“…It has been suggested that the nitro-reductive intermediates of nitrofuran derivatives are genotoxic [2,18,19]. The metabolite, which binds to protein covalently, is formed during the reductive metabolism of FZ in the livers of rats and pigs [20,21], as well as in the livers of turkeys and chickens [17,22]. It has also been suggested that the reductive metabolites of FZ bind to proteins as well as glutathione and react with DNA, consequently relating to the cytotoxicity that is exerted by several different mechanisms in Caco-2, HEp-2, and V79 cell lines [21].…”

“…The metabolite, which binds to protein covalently, is formed during the reductive metabolism of FZ in the livers of rats and pigs [20,21], as well as in the livers of turkeys and chickens [17,22]. It has also been suggested that the reductive metabolites of FZ bind to proteins as well as glutathione and react with DNA, consequently relating to the cytotoxicity that is exerted by several different mechanisms in Caco-2, HEp-2, and V79 cell lines [21]. FZ is therefore considered to have manifold bioactivities through initial nitro reduction and subsequent metabolic activations in vivo.…”

“…Nitrofuran derivatives (including FZ) were reduced at the nitro group in the initial step of their biotransformation, and continued to undergo further reduction of the nitro group whereas other parts of these compounds might be metabolized in many different ways [16,21,29].…”