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Folate Deficiency and Formiminoglutamic Acid Excretion during Chronic Diethylnitrosamine Administration to Rats¹

Institut du Cancer de Montréal, Hôpital Notre-Dame et Département de Biochimie, Université de Montréal [L. A. P.], and Department of Haematology, and McGill University Medical Clinic, Montreal General Hospital [V. M. W.], Montréal, Québec, Canada

Elevated levels of the histidine catabolite formiminoglutamic acid were excreted into the urine of rats that were given both 0.01% diethylnitrosamine in their drinking water for 1 to 5 weeks and an injection of a loading dose of histidine. Similar histidine loading of control rats that received no carcinogen did not produce an elevation in urinary formiminoglutamic acid excretion. The elevation in urinary formiminoglutamic acid excretion caused by chronic diethylnitrosamine administration was prevented by high dietary levels of the methyl donors, methionine, betaine, and choline; high dietary levels of folate and vitamin B₁₂, either alone or in combination, had no significant effect on the elevated formiminoglutamic acid excretion caused by diethylnitrosamine.

The elevated formiminoglutamic acid excretion caused by the administration of diethylnitrosamine for 3 weeks was associated with a decrease in the hepatic levels of the enzymes, formiminoglutamic acid transferase and urocanase, and with a decreased hepatic content of the higher conjugates of folate. Whereas dietary methionine administration completely prevented this decrease in the hepatic content of the higher conjugates of folate, dietary folate had no effect. Diets that contained elevated levels of methionine and choline also led to only a slight reversal of the decreased hepatic formiminoglutamic acid transferase activity caused by diethylnitrosamine. Thus the antagonistic effects on formiminoglutamic acid excretion by diethylnitrosamine and the methyl donors appeared to be mediated through the hepatic content of folic acid cofactors.

¹ Supported by grants from the National Cancer Institute and the Medical Research Council of Canada, and the Conseil de la Recherche Médicale de Québec.

² Present address: National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 7/12/72. Accepted 11/ 3/72.