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The Effect of Cysteine on the Metabolic Changes Produced by Two Carcinogenic N-Nitrosodialkylamines in Rat Liver

( Department of Biochemistry, Antoni van Leeuwenhoek-Huis: The Netherlands Cancer Institute, Amsterdam, The Netherlands)

Of the two N-nitrosodialkylamines studied, intravenous injection of diethylnitrosamine (DENA) produced a smaller inhibition of the in vitro incorporation of amino acids into the proteins of the microsomal-soluble fraction of rat liver than did administration of dimethylnitrosamine (DMNA). The liver glycogen was reduced in amount to a greater extent by DMNA than by DENA.

Pretreatment of the rats with excess cysteine for 2 days markedly reduced both the percentage inhibition of amino acid incorporation and the glycogenolysis produced by DMNA. No such effects of cysteine were observed in the case of DENA. The microsomal N-demethylase of the cysteine-livers, which probably initiates the conversion of DMNA to its actual toxic derivative, diazomethane, was markedly reduced in activity as compared with the enzyme of normal liver. Such was, however, not the case with the microsomal N-deethylase, which initiates the conversion of DENA to diazoethane.

The later findings may explain the differential effect of cysteine on the metabolic changes produced by the two N-nitrosodialkylamines in rat liver and provide strong evidence for the mechanism by which the latter compounds are converted to their toxic and carcinogenic derivatives.

Cysteine pretreatment also secured the survival of more than 50 per cent of the rats which received a lethal dose of DMNA.

The results are discussed, and it is concluded that both the toxic and the carcinogenic effects of the N-nitrosodialkylamines are due to the in situ formation of diazoalkanes, which are alkylating agents and appear to interact primarily with the endoplasmic reticulum of the liver cells.

Received 10/ 4/61.