1-Methyl-1-nitrosourea Depression of Brain Nicotinamide Adenine Dinucleotide in the Production of Neurologic Toxicity

Abstract

1-Methyl-1-nitrosourea (MNU) has been shown to be both a potent carcinogenic and antitumor compound (1, 2). These effects have been attribted to the liberation of diazomethane, a highly reactive agent capable of alkylating protein, RNA, DNA, and inhibiting the incorporation of amino acids into protein (3, 4). Recent investigations demonstrated that MNU can produce a rapid dose-related depression in liver nicotinamide-adenine dinucleotide (NAD) concentrations 5, 6). During the course of these studies there appeared a transient neurologic syndrome which was temporally related to the acute lowering of brain NAD levels. This communication correlates these findings with measurements of drug concentration in the acid-soluble fraction of brain, and with brain NAD glycohydrolase activity and histology.Methods. Male albino mice, Swiss strain, weighing 20-25 g were used for all studies, and were maintained on Purina laboratory chow pellets and water ad libitum. 1-Methyl-1-nitrosourea, NCS-23909, and nicotinamide (C...