Dietary effects of the pharmacokinetics of three carcinogenic nitrosamines (original) (raw)

1978, Toxicology and Applied Pharmacology

The concentrations of N-nitrosodimethylamine (DMN), N-nitrosodiethylamine (DEN), and N-nitrosodibmylamine (DBN) were monitored as a function of time in the blood and liver of rats fed either a normal diet or a diet marginally deficient in hpotropes. The disappearance of each nitrosamine from the blood showed first-order kinetics. Hepatic clearance of DEN and DBN also followed first-order kinetics, but the time dependence of DMN concentration in liver tissue showed an anomalous behavior. Diet-related differences in the pharmacokinetic data did not explain the variations in carcinogenicity caused by diet. Epidemiological studies have identified a number of well-defined geographical areas in which populations have a greater or smaller than average risk of developing certain cancers and have suggested that, in some cases, nutrients or foods may be the responsible factors (National Cancer Institute/American Cancer Society, 1975; Alcantara and Speckmann, 1976). In the United States one large group with varying degrees of nutritional deficiency consists of people having fatty livers and/or cirrhosis secondary to alcoholism. This group also has an increased risk of developing hepatic or esophageal cancer (Steiner, 1960; Wynder and Bross, 196 1). Severe lipotrope deficiency in rats provides a good experimental model for nutritional or alcoholic liver disease, but this condition does not support the longevity or weight gain necessary for carcinogenesis studies. A diet that is only marginally deficient in lipotropes, niacin, and amino acids and high in fat, however, supports nearly normal weight gain and enhances induction of hepatic, esophageal, or colon tumors by aflatoxin Bi (AFBJ, jV-nitrosodiethylamine (DEN), N-nitrosodibutylamine (DBN), N-2-fluorenylacetamide (AAF), 1,2-dimethylhydrazine (DMH), and 3,3-diphenyl-3-(dimethylcarbamoyl)1-propyne (DDCP) (Rogers and Newberne, 197la, 1973a, 1975; Rogers et aI., 1974; Rogers, 1975). Induction of bladder or gastric tumors by DBN, ZV-[4-(5nitro-2-fury&2-thiazolyllformamide (FANFT), DDCP, or N-methyl-N'-nitro-ZV-nitrosoguanidine (MNNG) and induction of liver tumors by iV-nitrosodimethylamine (DMN)