Damage to Mammalian Cell DNA by Nitrofurans

Abstract

<p>Nitrofurans, initially developed in the 1940's as antibacterial agents, have recently been shown to be mutagens and carcinogens. Present studies indicate that DNA may be an important target and that reductive 'activation' of the nitrofurans is likely before DNA damage occurs.</p> <p>Mammalian cells contain the enzymes necessry for reduction of nitrofurans, a process which occurs at maximum rates under anaerobic conditions. Toxicity of nitrofurans, as measured by cell survival, is maximum under nitrogen, and is also dependent on temperature, medium of incubation and position of the cell in the growth cycle. ATP and DNA synthesis are inhibited in air as well as nitrogen, while RNA and protein synthesis are often elevated in air but not in nitrogen. Phytohemaglutinin stimulation of human lymphocytes is inhibited when these cells are incubated with nitrofurans under nitrogen prior to stimulation/</p> <p>DNA single-strand breaks can be found in several cultured mammalian cell lines after incubation with nitrofurans. The extent of damage is dependent upon the oxygen concentration, nitrofuran used, drug concentration (including drug/cell ratio), and the duration of exposure. Rejoining of breaks is influenced by the extend of damage with proprtionately less repair after extensive breakage. Ascited cells incubated with nitrofurans in situ also show single-strand breaks which can be rejoined following elimination of the drug.</p> <p>Cells irradiated with UV or gamma rays, then incubated with nitrofurans, show enhanced damage (single strand breaks, or cell death) when incubation occurs in air or nitrogen. The position of the cell in the growth cycle influences the extent of DNA damage with cells being most sensitive at the G1/S interface. Plateau phase cells are more sensitive to such damage than exponentially growing cells.</p> <p>Some organs of mice labelled with radioactive thymide show a loss of radioactivity following nitrofuran feeding. It is not possible to conclude whether this loss is due exclusively to cell death and replacement, or to repair of damaged DNA. This decrease occurs in a biphasic manner, with rapid initial loss that suggests DNA repair as well as cell replacement.</p>