Counteraction by sulphydryl compounds of the enzymic conversion of and the metabolic lesions produced by two carcinogenic N-nitrosodialkylamines in rat liver

Abstract

(1) The in vivo and in vitro effects of various sulphydryl compounds on the metabolic conversion (N-dealkylation) of the N-nitrosodialkylamines, DMNA∗ and DENA, to their toxic and suspected carcinogenic derivatives by rat liver microsomes, were studied. MAB and EAB were included for comparison. Subcutaneous administration of excess cysteine to rats during 2 days leads to a decrease in the activity of the N-demethylating but not of the N-de-ethylating enzymes of the microsomes. Addition of cysteine and cysteamine, but not of reduced glutathione. to normal liver microsomes causes an inhibition of both types of enzymes, the N-de-ethylating being less susceptible than the N-demethylating enzymes. The latter finding may explain the differential effect observed after subcutaneous administration of cysteine. (2) The inhibitions of the in vitro amino acid incorporation into liver microsomes following administration of DMNA, DENA or CB 2446 are either completely prevented or reduced following injection of cysteamine, the degree of the latter effect being dependent on the route of application and the dose of cysteamine, and on the nature of the alkyl groups of the nitrosamines. Intravenously administered cysteine is less effective than cysteamine. The N-dealkylating enzymes of liver microsomes of rats treated with the cysteamine regimen which prevented the inhibition of amino acid incorporation by the nitrosamines, are not reduced in activity. (3) The glycogenolysis produced in liver by the intravenous administration of cysteamine and cysteine is counteracted by DMNA and DENA. (4) The results suggest that a mutual elimination of sulphydryl compounds and nitrosamine metabolites may occur in the livers of rats receiving dialkylnitrosamines and cysteamine or cysteine.