Aberrant Methylation of DNA As an Effect of Cytotoxic Agents

Abstract

Hydrazine (H₂N-NH₂) is a strong reducing agent, widely used in large amounts as an anticorrosive agent, as an intermediate in chemical syntheses, and as a propellant fuel. The compound at a single, high dose is neurotoxic, producing convulsions and respiratory arrest; at a lower single dose, hydrazine produces marked damage to the liver and kidneys (1,2). In a number of in vitro and in vivo tests, hydrazine, at relatively low concentration (dose), was positive as a mutagen (3–7). Chronic oral administration of hydrazine, at doses which depressed growth rate, produced pulmonary carcinomas in mice (8) and hepatocellular carcinomas and lung adenocarcinomas in rats and mice (9). When administered by inhalation at four different doses to rats, mice, and hamsters for 6 hr/d, 5 d/wk for 1 yr, hydrazine (only at the maximum tolerated dose) induced microscopic squamous cell carcinomas in the nasal turbinates of rats but no tumors in mice or hamsters (10). Hydrazine is capable of reacting in vitro under severe conditions with pyrimidine bases in DNA nucleotides to form the dihydro- or 4-hydrazino-derivatives or to open the pyrimidine rings (11). No one has yet been able to demonstrate a hydrazine-DNA adduct under in vivo conditions.