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PubMed1994

Ectopic pituitary grafts modify the response of male rats to sex differentiated promotion of diethylnitrosamine-initiated hepatic lesions with a choline-deficient diet.

The influence of implantation of ectopic pituitary grafts (PGs) under the kidney capsule in male rats on the sex differences in response to promotion with a choline-deficient (CD) diet was studied in the livers of diethylnitrosamine (DEN)-initiated Wistar rats. Growth of enzyme-altered foci, liver regeneration in response to partial hepatectomy (PH) and hepatic c-myc expression were studied. The area per enzyme-altered focus was significantly larger in initiated males fed a CD diet for 10 weeks when compared with the corresponding females. The sex difference was more pronounced 1 week after a PH performed following 10 weeks on the diet. In males carrying PGs the area per focus was reduced to the same size as in females. Liver weight gain after PH was reduced in males, but not in females, by the CD diet, and the level in PG-bearing males was intermediary, significantly different from that of males without grafts. A significantly lower labeling index in surrounding, but not in focal, hepatocytes was observed in initiated, CD-treated males than in the corresponding females 1 week after PH. In initiated as well as in uninitiated males on a CD diet the expression of the c-myc gene was 3- to 4-fold higher when compared with males fed a choline-supplemented diet at the time of PH. The mRNA level in females fed a CD diet was approximately 2.5-fold lower than in males, but still significantly above the level in females without the dietary treatment. A significant decrease in male c-myc expression was observed as a result of implantation of ectopic pituitaries. In conclusion, sex-differentiated promotion of DEN-initiated lesions with a CD diet is regulated by a pituitary influence on rat liver, in analogy with results previously obtained in the resistant hepatocyte model and with dietary deoxycholic acid promotion. This might suggest that pituitary factors are major determinants of sex-differentiated promotion in rat liver.

Animals↗
PubMed1994

Prevention by acetylsalicylic acid of liver cirrhosis and carcinogenesis as well as generations of 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances caused by a choline-deficient, L-amino acid-defined diet in rats.

Effects of acetylsalicylic acid (ASA) (aspirin) on the pathogenesis of fatty liver, cirrhosis and hepatocarcinogenesis caused by a choline-deficient L-amino acid-defined (CDAA) diet were examined in male Fischer 344 rats fed a CDAA diet supplemented with 0, 0.1, 0.2, 0.4 or 0.8% ASA for 30 weeks. ASA at concentrations of > 0.2% prevented the development of both cirrhosis and preneoplastic and neoplastic nodules, but without any directly associated prevention of fatty changes. ASA also prevented hepatocyte proliferation and the generation of thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine caused by feeding the CDAA diet, analyzed, respectively, after 1, 12 and 12 weeks. The results clearly indicate that the anti-inflammatory drug ASA, which is not a lipotropic factor, can prevent the pathogenesis of cirrhosis and hepatocarcinogenesis caused by a CDAA diet, which is possibly partly associated with the prevention of reactive oxygen species production.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1985

Lipid peroxidation of liver microsome membranes induced by choline-deficient diets and its relationship to the diet-induced promotion of the induction of gamma-glutamyltranspeptidase-positive foci.

The effects of varying the type of dietary fat in the choline-deficient (CD) diet on the development of gamma-glutamyltranspeptidase (GGT)-positive foci in the liver of carcinogen-treated rats were investigated, and the results were correlated with the extent of membrane lipid peroxidation induced by the diets. Male Sprague Dawley rats were initiated with a single dose of diethylnitrosamine. Thereafter, groups of rats were fed choline-supplemented or CD diets in which the amount of saturated fat was varied by using hydrogenated vegetable oil (Primex) and corn oil (CO), either alone or in combination. The number and size of GGT-positive foci induced by the CD diet with CO as the sole source of fat were larger than those induced by the diet containing mixtures of Primex and CO. The CD diet with Primex alone was the least effective in inducing GGT-positive foci. Peroxidation of liver microsomal membrane lipids in rats fed regular CD or CD:CO diets was examined by determining the formation of conjugated dienes. The generation of diene conjugate in rats fed a CD:CO diet was evident after 2 days of the diet feeding, and the levels increased at 1 and 2 weeks. No significant diene conjugate was demonstrated in rats fed a regular CD diet for 2 days. However, after 1 and 2 weeks, there was generation of diene conjugate, the levels of which were lower in rats fed the CD diet than those on a CD:CO diet. Addition of an antioxidant, 0.25% butylated hydroxytoluene, to both CD and CD:CO diets abolished the generation of diene conjugate in rat liver microsomal membranes and markedly inhibited the promotion of GGT-positive foci in the liver of diethylnitrosamine-initiated rats. The results suggest that membrane lipid peroxidation in the liver may be related to the promotion of the induction of GGT-positive foci by a CD diet. The enhanced promotion by the inclusion of a higher level of polyunsaturated fat in the diet may be, in part, due to its greater susceptibility to peroxidation.

Animals↗
PubMed1993

Dietary carotenoids influenced biochemical but not morphological changes in adult male rats fed a choline-deficient diet.

In a study of the effects of carotenoids, canthaxanthin (CA), beta-apo-8'-carotenal (BA), or beta-carotene in an extract of Spirulina-Dunaliella algae (AE) was fed at 0%, 0.1%, or 0.2% in a choline-deficient (CD) diet. In each of eight groups, 10 adult male Fischer 344 rats were fed diets with designated carotenoid sources and levels or a choline-sufficient diet for 12 weeks. Carotenoids altered some of the changes induced by the CD diet. Increases in enlargement of fatty livers and low plasma cholesterol levels occurred in rats fed 0.2% BA. Plasma retinol was further reduced 35% by BA or AE. BA and AE increased liver total vitamin A about 80% and 305%, respectively. Liver lipid peroxidation was enhanced and plasma alpha-tocopherol was reduced further by 1.0% AE. AE, BA, and CA (mg/g fat) depressed liver alpha-tocopherol about 49%, 67%, and 78%, respectively. The decreased liver alpha-tocopherol was concurrent with an increase in carotenoid stores of CA > BA > AE. Histopathological examination of sections of liver tissue by light microscopy showed fatty and cirrhotic changes in all rats fed CD diets. Histochemical evaluation based on a semiquantitative assay revealed a marked increase in peroxisome enzyme activity in the livers of all CD rats. None of the carotenoids appeared to have any effect on the development of morphological changes in the liver. Although carotenoids can function as antioxidants, they did not prevent changes observed in rats fed CD diets.

Alanine Transaminase↗
PubMed2006

Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet.

BACKGROUND/AIMS: Alcoholic liver disease is associated with nutritional deficiency and it may aggravate within the context of fatty liver. We investigated the relationship between alcohol intake (whiskey binge drinking) and a choline-deficient diet (CD) and assessed whether stellate cells could contribute to liver injury in this model. RESULTS: Rats fed the CD diet plus whiskey showed increased liver damage compared to rats fed the CD diet, as demonstrated by H&E staining, elevated transaminases, steatosis, TNF-alpha levels, enhanced CYP2E1 activity, impaired antioxidant defense, elevated lipid peroxidation, and protein carbonyls. The combined treatment triggered an apoptotic response as determined by elevated Bax, caspase-3 activity, cytochrome-c release, and decreased Bcl-2 and Bcl-XL. Stellate cells were activated as increased expression of alpha-Sma was observed over that by the CD diet alone. The combined treatment shifted extracellular matrix remodeling towards a pro-fibrogenic response due to up-regulation of collagen I, TIMP1, and Hsp47 proteins, along with down-regulation of MMP13, MMP2, and MMP9 expression, proteases which degrade collagen I. These events were accompanied by increased phosphorylation of p38, a kinase that elevates collagen I. CONCLUSIONS: Repeated alcohol binges in the context of mild steatosis may promote activation of stellate cells and contribute to liver injury.

Alcoholic Beverages↗
PubMed2006

Expression of inducible nitric oxide (NO) synthase but not prevention by its gene ablation of hepatocarcinogenesis with fibrosis caused by a choline-deficient, L-amino acid-defined diet in rats and mice.

Expression of inducible nitric oxide synthase (iNOS) and effects of iNOS gene ablation on the hepatocarcinogenesis associated with fibrosis caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male F344 rats and C57BL/6J wild-type and iNOS-/- mice. Western blot, RT-PCR and immunohistochemical analyses revealed increased expression of iNOS protein and mRNA in the livers of rats and wild-type mice fed a CDAA diet for 12-80 weeks, associated with elevated serum NO(x) and liver nitrotyrosine levels. iNOS-/- mice demonstrated greater liver injury and fibrosis in the early stage than their wild-type counterparts, but this did not significantly affect the incidence and multiplicity of altered foci, adenomas and hepatocellular carcinomas in spite of immunohistochemical iNOS expression in these lesions. Results suggested no major determinant roles of the expressed iNOS in the development of liver tumors caused by the CDAA diet.

Animals↗
PubMed1992

Expression of alpha, mu and pi class glutathione S-transferases in oval and ductal cells in liver of rats placed on a choline-deficient, ethionine-supplemented diet.

Expression of the alpha, mu and pi class glutathione S-transferases (GSTs) in hepatocytes, oval cells and ductal cells derived from the livers of rats placed on a choline-deficient, ethionine-supplemented (CDE) diet for 5 weeks was investigated. An overall decrease in the expression of alpha and mu class GSTs and an over-expression of pi class GST was observed in the liver after CDE treatment as indicated by Northern blotting analysis. Massive disruption of the liver with oval cell infiltration in the sinusoids throughout the lobule occurred after 5 weeks CDE treatment. 'Duct-like' structures consisting of oval-like cells (ductal cells) with rounder nuclei and more cytoplasm than oval cells within the sinusoids were also apparent. Immunocytochemical analysis revealed that the altered expression of GST in the whole liver is attributed to a differential expression of alpha, mu and pi class GSTs in the different cell types in the liver, including hepatocytes, oval cells around the portal region and among the sinusoids, and oval-like cells (ductal cells) in the 'duct-like' structures. In vitro studies using purified oval-ductal cells and hepatocyte populations confirmed the differential expression of GSTs in the varying cell populations in situ. The expression of the alpha and mu class GSTs in hepatocytes does not appear to be altered by the CDE diet. Heterogeneity in distribution of pi class GST was observed in the hepatocyte population, some hepatocytes were stained strongly while no staining was observed in others. Oval and ductal cells represent two distinct populations displaying different expression of GSTs. Pi class GST was detected in the majority of oval and ductal cells. Alpha class GST was detected in < 5% of the oval cell population and was found in > 50% of the ductal cell population. In contrast, mu class GST was absent in ductal cells and was present in 24% of oval cells around the portal region. This supports the view that ductal cells are not of bile ductal origin since mu GST is present in normal bile duct epithelial cells. Furthermore the change in expression of GSTs in the liver after CDE treatment is attributed to the large increase in oval and ductal cell populations.

Animals↗
PubMed2006

Diethanolamine and phenobarbital produce an altered pattern of methylation in GC-rich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency.

DNA methylation is an epigenetic mechanism regulating transcription, which when disrupted, can alter gene expression and contribute to carcinogenesis. Diethanolamine (DEA), a non-genotoxic alkanolamine, produces liver tumors in mice. Studies suggest DEA inhibits choline uptake and causes biochemical changes consistent with choline deficiency (CD). Rodents fed methyl-deficient diets exhibit altered methylation of hepatic DNA and an increase in liver tumors, e.g., CD causes liver tumors in B6C3F1 mice. We hypothesize that DEA-induced CD leads to altered methylation patterns which facilitates tumorigenesis. B6C3F1 hepatocytes in primary culture were grown in the presence of either 4.5 mM DEA, 3 mM Phenobarbital (PB), or CD media for 48 h. These concentrations induced comparable increases in DNA synthesis. PB, a nongenotoxic rodent liver carcinogen known to alter methylation in mouse liver, was included as a positive control. Global, average, DNA methylation status was not affected. The methylation status of GC-rich regions of DNA, which are often associated with promoter regions, were assessed via methylation-sensitive restriction digestion and arbitrarily primed PCR with capillary electrophoretic separation and detection of PCR products. DEA, PB, and CD treatments resulted in 54, 63, and 54 regions of altered methylation (RAMs), respectively, and the majority were hypomethylations. A high proportion of RAMs (72%) were identical when DEA was compared to CD. Similarly, 70% were identical between PB and CD. Altered patterns of methylation in GC-rich regions induced by DEA and PB resemble that of CD and indicate that altered DNA methylation is an epigenetic mechanism involved in the facilitation of mouse liver tumorigenesis.

Animals↗
PubMed2004

Inhibition of the development of hepatocellular carcinomas by phenyl N-tert-butyl nitrone in rats fed with a choline-deficient, L-amino acid-defined diet.

Effects of phenyl N-tert-butyl nitrone (PBN), a spin-trapping agent, on the development of frank cancers were examined in male Wistar rats fed with a choline-deficient, l-amino acid-defined (CDAA) diet for 70 weeks. PBN (0.065% in the drinking water) reduced incidences, multiplicities and possibly sizes of both hepatocellular adenomas and carcinomas when administered for all 70 weeks or only for the first 26 weeks, and those of carcinomas but not adenomas, when administered only for the last 44 weeks. These results indicate that PBN can prevent the development of frank HCCs in the CDAA diet model. The anti-carcinogenic effect of PBN may be ascribed to the prevention of both the development of HCAs and their malignant conversion to HCCs. If such findings can be generalized, PBN may be able to serve as a good tool to investigate molecular mechanisms underlying carcinogenic processes.

Adenoma↗
PubMed1994

Different roles of 8-hydroxyguanine formation and 2-thiobarbituric acid-reacting substance generation in the early phase of liver carcinogenesis induced by a choline-deficient, L-amino acid-defined diet in rats.

The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline-deficient, L-amino acid-defined (CDAA) diet by examining the effects of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8-hydroxy-guanine (8-OHGua) for DNA and that of 2-thiobarbituric acid-reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S-transferase (EC 2.5.1.18) placental form (GSTP)- and/or gamma-glutamyltransferase (GGT, EC 2.3.2.2)-positive lesions and levels of 8-OHGua and TBARS were determined. The GSTP-positive lesions of 0.08 mm2 or larger were all stained positively for GGT as well in cross-sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP-positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8-OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8-OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.

Animals↗
PubMed1987

Choline deficient diet enhances the initiating and promoting effects of methapyrilene hydrochloride in rat liver as assayed by the induction of gamma-glutamyltranspeptidase-positive hepatocyte foci.

Earlier we demonstrated that short-term feeding of methapyrilene hydrochloride (MPH) and of a choline deficient (CD) diet to rats induced peroxidative damage of microsomal membrane lipids of liver cells. In the present study, we investigated whether a CD diet modifies the extent of MPH-induced lipid peroxidation and whether the modifications lead to changes in the initiating and promoting action of these agents using assays of the induction of gamma-glutamyltranspeptidase (GGT)-positive hepatocyte foci. Addition of 0.1% MPH to a CD diet enhanced the extent of microsomal lipid peroxidation induced by a CD diet alone. Feeding a choline supplemented (CS) or a CD diet containing 0.1% MPH for 2 weeks followed by 7 weeks promotion by a CD diet plus phenobarbital was ineffective in inducing GGT-positive foci. Feeding MPH in a CS or a CD diet for 4 weeks, however, resulted in the development of substantial numbers of GGT-positive foci. There was a 3 fold increase in the number of foci in rats initiated with a CD + MPH diet over that in rats initiated with a CS + MPH diet. 0.1% MPH in a CS diet or a CD diet exerted significant promotional effects on the induction of GGT-positive foci in rats initiated with a single injection of diethylnitrosamine. Addition of MPH to a CD diet was additive in inducing GGT-positive foci. The results suggest that lipid peroxidation of the liver may be involved in the carcinogenic and/or promoting effects of MPH and a CD diet.

Aminopyridines↗
PubMed2004

The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance.

BACKGROUND/AIMS: Non-alcoholic steatohepatitis is an important disease whose pathophysiology remains incompletely understood, although in humans a strong association with insulin resistance exists. Mice fed a methionine-choline deficient (MCD) diet develop steatohepatitis, however the influence of insulin in this model is unknown. METHODS: Male FVB/NJ mice were fed the MCD, MCD control or chow diet for 10 or 28 days. Fasting glucose, ALT, triglyceride and insulin was measured. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed followed by quantitative insulin sensitivity check index (QUICKI) determination. RESULTS: ALT levels were significantly higher in the MCD group. Fasting glucose was 81+/-5 mg/dl in MCD diet fed mice, compared to MCD controls (196+/-46 mg/dl) and chow (199+/-15 mg/dl) (P<0.0001). During GTT and ITT, the effect of glucose administration on blood glucose was dampened, and the insulin effect more pronounced in the MCD group (P=0.026 and P<0.001). QUICKI in MCD fed mice was significantly higher than in the chow fed mice. CONCLUSIONS: GTT, ITT and QUICKI confirmed the absence of insulin resistance in the MCD fed mice. This model causes fibrosing steatohepatitis and may help delineate the non-insulin resistant mechanisms involved in human steatohepatitis.

Alanine Transaminase↗
PubMed2003

Effects of phenyl N-tert-butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined diet.

The present study examined the effects of various derivatives of a radical trapping agent, phenyl N-tert-butyl nitrone, on the early phase of hepatocarcinogenesis in male Wistar rats fed a choline-deficient, L-amino acid-defined diet for 16 weeks. The derivatives used were 4-hydroxyphenyl (a physiologically major metabolite), 3-hydroxyphenyl, 2-hydroxyphenyl and 2-sulfoxyphenyl N-tert-butyl nitrone, and their effects were studied in a comparison with those of the parent compound, phenyl N-tert-butyl nitrone. The sizes of putatively preneoplastic, glutathione S-transferase placental form-positive lesions and the levels of extra-nuclear oxidative injury of hepatocytes, using the formation of 2-thiobarbituric acid-reacting substances as a parameter, were decreased by all doses (0.009%, 0.045% and 0.090% in diet) of 4-hydroxyphenyl N-tert-butyl nitrone and only by the highest dose of 3-hydroxyphenyl N-tert-butyl nitrone and phenyl N-tert-butyl nitrone. While 4-hydroxyphenyl N-tert-butyl nitrone, 3-hydroxyphenyl N-tert-butyl nitrone and phenyl N-tert-butyl nitrone all enhanced and inhibited hepatocellular apoptosis in preneoplastic lesions and their surrounding tissue, respectively, only 4-hydroxyphenyl N-tert-butyl nitrone additionally inhibited hepatocyte proliferation both in preneoplastic lesions and their surrounding tissue. 2-Hydroxyphenyl or 2-sulfoxyphenyl N-tert-butyl nitrone did not exert any of the above effects. These results suggest that the selective induction of apoptosis in preneoplastic hepatocyte populations plays a crucial role in the inhibition of hepatocarcinogenesis derived by phenyl N-tert-butyl nitrone and its effective derivatives. Further, the metabolic conversion to 4-hydroxyphenyl N-tert-butyl nitrone may also be important for the inhibitory effects of phenyl N-tert-butyl nitrone on hepatocarcinogenesis.

Amino Acids↗
PubMed2000

Correlation between stellate cell activation and serum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis.

The aim of this study was to investigate the association of stellate cell activation with serum fibrosis markers in a rat model of hepatic fibrosis prepared using a choline-deficient L-amino acid (CDAA) defined diet. CDAA diet administration resulted in increased liver hydroxyproline contents in a time-dependent manner with activated stellate cells, expressing alpha-smooth muscle actin (alpha-SMA) as well as increased serum concentrations of amino-terminal procollagen type III peptide (PIIIP) and the 7S fragment of type IV collagen. Hydroxyproline content of the liver showed a closer correlation with the serum 7S (r = 0.75, P < 0.01) concentration than with the serum PIIIP (r = 0.51, P < 0.01) concentration. The percent area of alpha-SMA-positive cells showed stronger correlation with the serum PIIIP concentration (r = 0.85, P < 0.01) than with the 7S concentration (r = 0.50, P < 0.01). These results indicate that the serum PIIIP concentration reflects the activity of fibrogenesis, while the serum 7S concentration reflects the accumulation of collagen fibers in the liver.

Animals↗
PubMed2000

Absence of p16, p21 and p53 gene alterations in hepatocellular carcinomas induced by N-nitrosodiethylamine or a choline-deficient L-amino acid-defined diet in rats.

To clarify the involvement of tumor suppressor genes in exogenous and endogenous liver carcinogenesis, alterations of p16, p21 and p53 in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and a choline deficient L-amino acid-defined (CDAA) diet in rats were investigated. Male Fischer 344 rats received DEN at 6-week of age followed by partial hepatectomy (PH), with colchicine to induce cell cycle disturbance, and a selection pressure regimen. Sacrifice was after 42 weeks. Other animals continuously received a CDAA diet for 75 weeks and were then killed. Eleven and 15 HCCs were obtained, respectively. Total RNA was extracted from and cDNA was synthesized with reverse transcriptase to allow investigation of mutations in p16, p21 and p53 by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analysis. Expression of p16 and p21 mRNA was also analyzed by reverse transcription (RT)-PCR. The results showed no mutations or deletions of p16, p21 and p53 in any of the HCCs induced by DEN or CDAA. Loss or decrease of p16 and p21 expression were also not found, suggesting that p16, p21 and p53 alteration may not be necessary for either exogenous or endogenous liver carcinogenesis in rats.

Animals↗
PubMed1999

Iron chelator deferoxamine reduces preneoplastic lesions in liver induced by choline-deficient L-amino acid-defined diet in rats.

The aim of this study was to investigate whether an iron chelator, deferoxamine (DFO) can prevent lipid peroxidation, resulting in reduced liver injury as well as reducing preneoplastic lesions induced by a choline-deficient L-amino acid-defined (CDAA) diet. CDAA diet administration resulted in an increased serum ALT level (367 +/- 58) after two weeks, but simultaneous DFO treatment for two weeks reduced this elevation of ALT as well as malondialdehyde (MDA) production in the liver. Feeding rats a CDAA diet for 12 weeks led to the development of severe liver fibrosis and preneoplastic lesions detected as enzyme-altered lesions. DFO treatment prevented the expression of activated stellate cells, resulting in the reduction of liver fibrosis as well as reducing the development of preneoplastic lesions. These results indicate that iron chelation can reduce the development of preneoplastic lesions in a CDAA diet model.

Alanine Transaminase↗
PubMed1993

Effects of chronic administration of low doses of 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline on glutathione S-transferase placental form-positive foci development in the livers of rats fed a choline-deficient diet.

Effects of chronic administration of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) at the very low doses of 0.4 and 4 ppm, respectively 1000- and 100-fold less than the dose shown to be carcinogenic (400 ppm), on the liver of rats fed a choline-deficient (CD) diet were examined in terms of glutathione S-transferase placental form (GST-P)-positive foci. Male F344 rats were given CD diet containing 0, 0.4 or 4 ppm MeIQx for 20 or 40 weeks. As controls, rats received choline-supplemented (CS) diet in the same manner. MeIQx at 4 ppm in the CD diet significantly increased both the number and area of GST-P-positive foci, the values being 2.3- and 2.1-fold at 20 weeks and 2.0- and 3.3-fold at 40 weeks, respectively, compared with those observed for CD diet alone. MeIQx at 0.4 ppm in CD diet did not affect the development of GST-P-positive foci. No influence of the heterocyclic amine was found in the CS groups, where only very small numbers of minute lesions were observed. The level of MeIQx-DNA adducts in rats given the CD diet containing 4 ppm MeIQx was 2- to 3-fold lower than that in rats given the CS diet containing 4 ppm MeIQx at 20 and 40 weeks. This result indicates that DNA adduct formation and cell proliferation are both required for the increase of GST-P-positive foci in rats fed 4 ppm MeIQx in a CD diet. The above findings strongly suggest that MeIQx could be carcinogenic even at 4 ppm under CD conditions, where liver cell regeneration is continuously occurring.

Animals↗