N,N-Dimethylformamide-induced effects on hepatic and renal xenobiotic enzymes with emphasis on aldehyde metabolism in the rat.

Abstract

Male Wistar rats were dosed with N,N-dimethylformamide (DMF) in drinking water at four concentration levels (0,0.1,0.5 or 1.0 g/l) for 2 or 7 weeks. Upon evaluation of the effects in the liver increased values were found for the following parameters: liver/body weight-ratio, GSH content, ethoxycoumarin O-deethylase and UDPglucuronosyltransferase activities. The GSH content, deethylase activity and, transiently, the glucuronidation activity were slightly increased also in the kidneys. Oxidative N-demethylation of DMF by hepatic microsomes in vitro was not enhanced by oral treatment. No DMF-dependent formaldehyde liberation in vitro could be detected under conditions where formaldehyde liberation from N,N-dimethylnitrosamine could be demonstrated. However, the endogenous rate of formaldehyde generation by liver microsomes isolated from DMF-treated rats was enhanced with the highest oral dose of DMF. The daily intake of DMF lowered the activities of both formaldehyde and propionaldehyde dehydrogenases in the liver soluble fraction. No inhibition of these dehydrogenases was shown in vitro by DMF (less than or equal to 10 mM) or by its main urinary metabolite N-methylformamide (less than or equal to 10 mM). The observed impairment of aldehyde oxidation in liver and kidneys of the rat after the DMF intake could explain the mechanism behind the alcohol intolerance observed in man after DMF-exposure.