Effects of varying the fat content of a choline-devoid diet on promotion of the emergence of γ-glutamyltranspeptidase positive foci in the liver of carcinogen-treated rats

Shinozuka, Hisashi; Takahashi, Sehchi; Lombardi, Benito; Abanobi, Samuel E.

doi:10.1016/0304-3835(82)90089-1

Cited by 28 publications

(39 citation statements)

References 11 publications

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“…The promoting activity of MPH was greater than that seen with a CD diet, and the combination of a CD diet and MPH acted additively in promoting the induction of GGT-positive foci. This is in contrast to our earlier observation that the combination of a CD diet and phenobarbital, a well known liver tumour promoter, resulted in a synergistic effect (Shinozuka & Lombardi, 1980). Based on the findings that while a CD diet induces membrane lipid peroxidation, phenobarbital shows no such effect, we postulated that the mechanisms of tumour promotion by a CD diet and phenobarbital are probably different (Shinozuka et al, 1985).…”

Section: Discussioncontrasting

confidence: 90%

“…After one week on Purina Chow, each group received a CD diet containing 0.06% PHB for 7 weeks (Groups I & II). The combination of a CD diet and phenobarbital has been shown to act synergistically for the induction of enzyme altered foci in the liver of carcinogen initiated rats (Shinozuka & Lombardi, 1980). For the last 4 days of the experiments, PHB was withdrawn from the diet in order to eliminate background activities of y-glutamyltranspeptidase (GGT) in hepatocytes.…”

Section: Determination Of Diene Conjugationmentioning

confidence: 99%

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

Perera

Katyal²,

Shinozuka³

1987

Br J Cancer

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Summary 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 y-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.Methapyrilene hydrochloride (MPH) is a competitive H1 histamine antagonist which has been shown to induce liver tumours in Fischer F344 rats after feeding for over a year . The mechanism of its carcinogenic action remains unclear. In short term in vivo animal studies, MPH acts as a promoter of the induction of enzyme altered foci and hepatomas in the liver of carcinogen initiated rats, but a single injection of MPH was ineffective in inducing foci in the liver when followed by a liver tumour promoter (Couri et al., 1982;Furuya et al., 1983). In several in vitro carcinogenicity tests such as the Salmonella mutagenesis test, the transformation assays with hamster embryo cells and the quantitation of induction of sister chromatid exchanges, MPH yielded negative results (Andrews et al., 1980;Pienta et al., 1977; lype et al., 1982). Although earlier reports indicated that MPH was ineffective in inducing DNA repair synthesis in cultured rat hepatocytes (Probst & Neil, 1980;McQueen & Williams, 1981), positive results were reported more recently (Althaus et al., 1982). There is no evidence to indicate that MPH or its metabolites covalently interact with cellular DNA (Lijinsky & Muschik, 1982).We demonstrated that MPH is a potent inducer of membrane lipid peroxidation in rat hepatocytes (Perera et al., 1985a). In a number of studies, free radical injury either leading to or deriving from peroxidative damage of lipids has been implicated as the underlying mechanism of carcinogenic and/or promotional actions of many agents (Pryor, 1973;Reddy & Warren, 1981;Troll et al., 1982;Cer...

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Section: Discussioncontrasting

confidence: 90%

Section: Determination Of Diene Conjugationmentioning

confidence: 99%

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

Perera

Katyal²,

Shinozuka³

1987

Br J Cancer

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“…EAF have been characterized extensively in the livers of rodents treated with carcinogens. [34][35][36][37][38][39][40] Enzyme alterations are also observed in the glandular stomach in carcinogen-treated rodents, so-called pepsinogen-altered pyloric glands (PAPG), also considered as a stomach precancerous lesion. [41][42][43][44][45][46][47] We confirmed alteration of hexosaminidase activity by staining of paraformaldehydefixed whole mounted colonic mucosa.…”

Section: Discussionmentioning

confidence: 99%

Hexosaminidase‐altered Aberrant Crypts, Carrying Decreased Hexosaminidase α and β Subunit mRNAs, in Colon of 1,2‐Dimethylhydrazine‐treated Rats

Tsukamoto

Fukami

Yamanaka

et al. 2001

Japanese Journal of Cancer Research

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Aberrant crypt foci (ACF), consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancers. For their molecular analysis, it is necessary to avoid contamination with adjacent normal crypts and stromal cells. Decreased hexosaminidase activity in ACF, which has been histochemically demonstrated, was used in the present study to classify isolated crypts in combination with morphological changes. The length, rim diameter, and width (average ± ± ± ±SD, µ µ µ µm) of hexosaminidase-positive (Hex + + + +) crypts were 238.6 ± ± ± ±40.4, 89.5 ± ± ± ±22.9, and 57.6 ± ± ± ±14.0, respectively. For hexosaminidase-negative (Hex − − − −) crypts, the values were 314.4 ± ± ± ±77.8, 140.3 ± ± ± ±45.7, and 97.3 ± ± ± ±34.7, the width being 1.69 times greater (P < < < <0.0001).

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“…More recently, we found that inclusions of PHB in a CD diet resulted in a synergistic effect of the two agents (10). Indeed, in rats exposed to a single injection of diethylnitrosamine (DEN), foci of hepatocytes developed in a number greater than the sum of those observed in rats treated with either agent alone.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Tumor Promotion in Liver Carcinogenesis

Satoh¹,

Abanobi²,

Lombardi³

1983

Environmental Health Perspectives

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Earlier, we demonstrated that feeding to rats a diet devoid of choline, a lipotropic factor, markedly enhances hepatoma induction by several chemical carcinogens, and that the diet acts as a strong promoter of the evolution of initiated cells to foci of altered hepatocytes. The ability of several factors to modulate the action of the choline-devoid (CD) diet as a promoter was investigated by quantitating the foci of y-glutamyl transpeptidase-positive hepatocytes developed in rats exposed to a single injection of diethylnitrosamine. Addition to the diet of phenobarbital (PHB) resulted in a promoting action stronger than those of the CD diet or of PHB alone. Two other barbiturates, amobarbital (AMB) and pentobarbital (PTB) exerted an effect similar to that of PHB, while barbituric acid (BA) had no effect. In other studies, lowering the fat content of the CD diet reduced its efficacy as a promotor, while the addition of a hypolipidemic agent, BR931, 4-chloro-642,3 xylidino)-2-pyrimidinylthio (N-p-hydroxy-ethyl)acetamide, completely abolished the promoting action of the CD diet. In rats not exposed to carcinogen, feeding the CD diet caused a marked enhancement of liver DNA synthesis and of cell proliferation. Inclusion of PHB, PTB or AMB in the CD diet inhibited these effects, while BA exerted no inhibition. The increased rate of DNA synthesis and cell proliferation in the liver were not affected by the level of fat in the CD diet. These results suggest that beside a stimulation of liver cell proliferation, other factor(s) determine the efficacy with which a CD diet exerts its promoting action.

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Effects of varying the fat content of a choline-devoid diet on promotion of the emergence of γ-glutamyltranspeptidase positive foci in the liver of carcinogen-treated rats

Cited by 28 publications

References 11 publications

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

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

Hexosaminidase‐altered Aberrant Crypts, Carrying Decreased Hexosaminidase α and β Subunit mRNAs, in Colon of 1,2‐Dimethylhydrazine‐treated Rats

Modulation of Tumor Promotion in Liver Carcinogenesis

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