methylnitronitrosoguanidine and Vitamin-A-Deficiency

We studied the characteristics and mechanisms of MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) intestinal absorption and the interaction between bile acids and fatty acids and MNNG absorption rate in vivo in male Sprague-Dawley rats. We perfused a segment of the proximal small bowel with a physiological solution containing MNNG to assess its basic kinetics and the influence of some physiological and dietary factors on carcinogen absorption. We found that MNNG was absorbed by simple passive diffusion. Transport of MNNG was the highest at pH 6.0. The addition of the bile salt, taurocholate by itself, greatly increased MNNG absorption, while the addition of the long-chain unsaturated fatty acids, oleic and linoleic, decreased the rate of absorption of MNNG. The phospholipid lecithin addition to the perfusate did not change the rate of MNNG absorption. Induction of dietary vitamin A deficiency (serum vitamin A level decreased from 40.9 to 13.7 micrograms/dl) did not change the absorption rate of MNNG. These studies demonstrate that bile acids, dietary fatty acids, and the pH of the intestinal content can modify the rate of absorption of this carcinogen by the small intestine. Since initial intestinal absorption determines serum levels and subsequent reabsorption and enterohepatic cycling determines long-term lumenal levels, serum levels, and total body content, factors which modify the rate of intestinal absorption of MNNG could also modify its carcinogenicity.

Topics: Animals; Bile Acids and Salts; Cell Membrane; Diffusion; Fatty Acids; Fatty Acids, Unsaturated; Hydrogen-Ion Concentration; Intestinal Absorption; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Taurocholic Acid; Vitamin A Deficiency

The effect of vitamin A deficiency on the sensitivity of the colon to the carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a direct-acting carcinogen, given intrarectally was studied in female Fischer rats. Animals maintained on Purina laboratory chow, semipurified vitamin A-free diet, or semipurified vitamine A-supplemented diet were given intrarectally 1.25, 0.63, or 0.31 mg MNNG 3 times weekly for 30 weeks and autopsied at the 45th week. The number of large bowel tumors per tumor-bearing rat was higher in animals receiving 1.25 mg MNNG compared to those given 0.63 or 0.31 mg. Vitamin A deficiency in rats given 1.25 mg MNNG significantly suppressed the large bowel tumor induction compared to rats fed adequate vitamin A. A high incidence of squamous cell papillomatosis of the urinary bladder was observed in rats fed vitamin A-free diet and given 1.25 mg MNNG. The present experiment suggests that the large intestine has a susceptibility that is different from that of the respiratory and urinary tracts to tumorigenic stimulation in vitamin A-deficient status.

Topics: Animals; Colonic Neoplasms; Female; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Papilloma; Rats; Urinary Bladder Neoplasms; Vitamin A Deficiency