Inhibition of microsomal N-nitrosodimethylamine demethylase by diethyl ether and other anesthetics.

ABSTRACT

The inhibitory actions of diethyl ether and several other anesthetics on the metabolism of N-nitrosodimethylamine (NDMA) and other substrates were studied with rat liver microsomes. Diethyl ether was an effective inhibitor of the low Km NDMA demethylase, showing characteristics of a competitive inhibition. Inhibition of NDMA metabolism was also observed in the liver post-mitochondrial supernatant fraction prepared from ether-anesthetized rats. Selectivity in the inhibitory action of diethyl ether was demonstrated; the ether was most effective against NDMA demethylase, less potent against p-nitroanisole demethylase and N-nitrosomethylbenzylamine demethylase, and not effective against the metabolism of aminopyrine or benzphetamine. Other anesthetics such as chloroform, isoflurane, enflurane, and halothane also effectively inhibited NDMA demethylase. The work demonstrates that diethyl ether is an efficient inhibitor of NDMA metabolism by the microsomal monooxygenase systems.