Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets

Abstract

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)

Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma

“…Experimental studies have shown that diets deficient in methyl groups (folate, methionine, and choline) can induce HCC in rodents 9,10 along with an increased level of uracil in DNA and accumulated DNA strand breaks in the P53 gene of the hepatocytes. [11][12][13] Thymidylate is a rate-limiting nucleotide required for DNA synthesis and repair.…”

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas

“…For these reasons, induction of folate/methyl deficiency in rats requires diets devoid of folate and choline, and low in methionine. It is also well established that this diet deficient in choline and methionine results in the development of hepatocellular carcinomas in rats (Mikol et al, 1983;Ghoshal et al, 1987). This is, therefore, considered an ideal animal model to study multistage hepatocarcinogenesis in that it mimics the metabolic alterations caused by genetic and/or nutritional deficiencies in folate/choline/methionine in humans (Wainfan et al, 1988(Wainfan et al, , 1989James and Yin, 1989;James et al, 1992;Pogribny et al, 1995Pogribny et al, , 1997.…”

No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet

“…F or instance, the induction of liver tumors in rats by peroxisome proliferators (Rao and Reddy, 1987) Abbreviations: dNp, deoxyribonucleoside-3'-phosphate; cisdTGp, cis-thymidine glycol-3'-phosphate; 8-0H-dG, 8-hydroxy-deoxyguanosine; ECD, electrochemical detection. cient diet (Mikol et al, 1983;Goshal and Farber, 1984) is often considered to be due to increased oxidative DNA damage.…”