The ability of methyl-deficient, amino acid-defined diets to produce liver tumors was studied in rats treated both with and without initiating doses of diethylnitrosamine (DENA). Male, weanling F344 rats were fed a complete, amino acid-defined diet for one week. They were then injected once i.p. with one of 3 doses of DENA (20, 70 or 200 mg/kg body weight) and fed the complete diet for an additional week. Thirty animals from each dose group were then maintained for 76 weeks on the complete diet (Diet 1) or one of 4 methyl-deficient diets: Diet 2, devoid of methionine and choline; Diet 3, devoid of methionine only; Diet 4, devoid of choline only and Diet 5, devoid of methionine, choline, folic acid and vitamin B12. In Diets 2, 3 and 5 methionine was replaced by equimolar amounts of its metabolic precursor DL-homocystine. Control rats were injected i.p. with the saline vehicle and maintained for the 76-week period on Diets 1 and 2. Forty percent of the rats fed Diet 2, but receiving no DENA, developed hepatocellular carcinomas or cholangiomas. A 90-100% incidence of hepatocellular carcinomas was seen in all groups initiated with DENA and fed Diet 2. No malignant liver tumors developed in Diet 1 rats that had received 0 or 20 mg/kg DENA; however, hepatocellular carcinomas were noted in one-half of such animals receiving the 70 and 200 mg/kg doses. Liver metastases grew in the lungs of 60% of the tumor-bearing rats fed Diet 2; none were seen in the Diet 1-fed rats. The singly deficient Diets 3 and 4 enhanced liver tumor formation to DENA-initiated rats to a significantly lesser extent than did Diet 2. All DENA-initiated rats fed the severely deficient Diet 5, died within 23 experimental weeks with livers containing hepatocytes of atypical appearance and, particularly at the 2 higher dosages, a cirrhotic pseudonodular architecture. No hepatocellular carcinomas or cholangiomas were observed in Diet 5-fed rats. None of the diets tested appeared to enhance tumor formation in extrahepatic tissues. In fact, significant decreases were noted in the formation of spontaneous testicular interstitial cell tumors in Diet 2-fed rats and of pancreatic acinar tumors in rats fed Diets 2 and 3. Diet 2, devoid of both methionine and choline, also induced metaplasia of pancreatic acinar cells to hepatocyte-like cells and was associated with moderate to severe hyperplasia of the transitional epithelium lining the renal pelvis.(ABSTRACT TRUNCATED AT 400 WORDS)
Seven groups of 4-week-old male Sprague-Dawley rats, 30 animals/group, were fed for 18 months a commercial chow diet with or without 1% admixture of lead subacetate (Pb-Acet) and 0, 0.3, 1, 3 and 6% of calcium acetate (CaAcet). Feeding a 3% CaAcet-only diet did not produce any pathomorphological effects except for a slight decrease in body weights of the rats to 93% of that seen in the control rats. Feeding the 1% PbAcet-only diet decreased the growth rate of rats to 80% that of the control animals and increased the organ/body weight ratios of the kidneys and livers to 200% and 114% of the corresponding control values. Kidney tumors developed in 45% of the rats treated with PbAcet only, with the earliest appearing at 58 weeks. No tumors of other tissues were found in those rats. Feeding the PbAcet + CaAcet diets reduced the weights of rats from 74% to 54% of that of the control rats and increased the kidney/body weight ratio to 300% that of the control animals. The incidences of renal tumors increased in those rats to an average of 71% (p less than 0.03 versus the PbAcet-only diet), with no significant effects relative to the CaAcet contents in the diets. Primary non-renal tumors were found only occasionally in rats fed the PbAcet + CaAcet diets, without significant differences among the various treatment groups. The renal lead accumulation at 18 months equalled 572 +/- 102, 295 +/- 43, 247 +/- 10, 168 +/- 9, and 162 +/- 6 micrograms/g dry weight (mean +/- S.E.M.; n = 22-24) for the 0, 0.3, 1, 3 and 6% CaAcet in the PbAcet diet, respectively. The hepatic accumulation of lead was 22.2 +/- 0.7 micrograms/g dry weight with no discernible differences among the various PbAcet + CaAcet treatment groups. The results indicate that CaAcet added to the PbAcet diet increases the toxicity of the lead salt, and tends to enhance the renal carcinogenicity of PbAcet, yet decreases the accumulation of lead in the kidneys. No significant adverse effects of the PbAcet and CaAcet treatments on the livers were found.
The effect of the chronic feeding of methionine or choline on liver tumor promotion by phenobarbital (PhB) or 1,1 bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT) was studied in rats receiving an initiating dose of diethylnitrosamine (DEN). Male weanling rats were injected i.p. with DEN (200 mg/kg body wt). Control rats were injected with saline. Five days after the injection, the rats were placed on different diets containing 0.05% PhB or 0.05% DDT with or without added 1.5% DL-methionine or 1.0% choline chloride. Each diet was administered for 72 weeks, when the animals were placed on the unsupplemented chow diet for an additional 30 weeks. Rats treated with DEN and then fed PhB or DDT developed an 85-100% incidence of hepatocellular carcinomas (HCCs). Single injection of DEN alone produced a 60% incidence of HCCs. Dietary feeding of methionine and choline either alone or in combination with PhB or DDT did not have any significant effect on the incidence of HCC's. Liver tumor formation was negligible in uninitiated rats. Lung metastases developed in 42% and 46% of the DEN + PhB- and DEN + DDT-treated groups, respectively. Supplementation of methionine in the diet lowered the incidence of lung metastases to 14% in the DEN + PhB-treated rats and to 19% in DEN + DDT-treated rats. Choline was not effective in inhibiting the development of lung metastases in either case. The injection of DEN alone produced a 54% incidence of lung tumors. PhB and DDT feeding lowered the DEN-induced lung tumor incidence to 23% and 14% respectively. Further, when the data from different diet groups were combined it was found that single injection of DEN also doubled the incidence of leukemia normally seen in F344 rats. The present report constitutes the first evidence that a single injection of DEN induces lung tumors and enhances the incidence of leukemia in rats.
Administration of a methyl-group-deficient diet with or without an initial single injection of diethylnitrosamine to male Fischer 344 rats resulted in the development of cells structurally similar to hepatocytes that lay in small clusters around one or more islets of Langerhans in the pancreas. These cells were detected in 15/256 rats fed various methyl-deficient diets in study 1 and in 7/28 rats fed a severely methyl-group-deficient diet in study 2. The results of special staining procedures for the detection of glycogen, albumin and particulate iron uptake indicated that at least some of these cells shared features common to liver cells. These results, as well as previously reported observations of similar cells in hamsters treated with ethionine, provide additional evidence that the lack of available physiological methyl donors contributes to altered differentiation of pancreatic acinar cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.