Toxic liver injury and carcinogenesis. Methylation of proteins of rat-liver slices by dimethylnitrosamine in vitro

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Abstract
The hepatotoxin and carcinogen dimethylnitrosamine, labelled with radioactive carbon, was incubated with rat-liver slices in vitro, and the fate of the label in some components of the acid-soluble protein and nucleic acid fractions of the tissue was studied. The radioactive liver protein was hydrolysed to free amino acids by hydrochloric acid, followed by ion-exchange column chromatography of the hydrolysate. Ion-exchange chromatography with better resolution of the basic amlno acids showed that hlstidine and lyslne were not labelled. Much of the radioactivity associated with them was resolved into two peaks which corresponded closely with carrier 1-methyl- and 3-methyl-histidine added to the protein hydrolysate before chromatography. Pechromatography of the 1-methyl- and 3-methyl-histidine peaks gave very close agreement between the profiles of radioactivity and concentration of amlno nitrogen. These results are consistent with the hypothesis that dlmethylnltrosamlne, after enzymlc oxidative N-demethylation, releases a methylating agent which methylates the imidazole group of some histidine residues and possibly also some free carboxyl groups of proteins. The carbon of the methyl group removed by oxidative demethylation appears to enter the general metabolic pool. The probable chemical alteration of tissue proteins by dimethylnitrosa-mlne is discussed in relation to some current theories of tissue injury and carcinogenesis.