Promotion of liver carcinogenesis in the rat by a choline-devoid diet: role of liver cell necrosis and regeneration.
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Animals↗
Biomedical subjects
B Lombardi
Publications and source records attributed to B Lombardi.
A comparative study of the efficacy of four barbiturates as promoters of the development of gamma-glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats.
The promoting action of four barbiturates, and their modulation of the promoting action of a choline-devoid (CD) diet was investigated by quantitating the gamma-glutamyltranspeptidase (GGT)-positive foci which developed in the liver of rats exposed to a single injection of diethylnitrosamine. Phenobarbital (PHB), pentobarbital (PTB) and amobarbital (AMB), exerted a promoting action, while barbituric acid (BA) had no effect. Addition of PHB or PTB to a CD diet resulted in a synergistic promoting action, but AMB had only an additive effect. Feeding a CD diet to rats caused a stimulation of liver DNA synthesis and of cell proliferation. These effects of the diet were markedly inhibited by addition of PHB or PTB, while addition of AMB resulted only in an inhibition of the enhanced proliferation of hepatocytes. No inhibitory effect was exerted by BA. The results indicate that the liver tumor promoting action of PHB and of barbiturates is dependent upon biological effects related to the presence of an alkyl group in their side chain. It is hypothesized that the promoting action of the agents herein studied may involve two components, a stimulation of the proliferation of initiated liver cells, and a suppression of the proliferation of non-initiated cells.
Animals↗
Acute hemorrhagic pancreatic necrosis in mice. Effects of proteinase inhibitors on its induction.
An acute hemorrhagic pancreatitis with fat necrosis (AHPN) was induced in female mice fed a choline-deficient diet containing 0.5% DL-ethionine. The effect of various proteinase inhibitors on the induction of the pancreatitis was evaluated using three parameters, the mortality of the animals, the appearance before death of a shock-like state, and the severity of the pancreatic pathology. Treatment of the animals with leupeptin, pepstatin, chymostatin and/or antipain, proteinase inhibitors of microbial origin, resulted in a distinct attenuation of the severity of the induced process, whereas aprotinin and chloroquine had no effect. The results indicate that use of the microbial proteinase inhibitors should be considered as potential therapeutic agents in cases of pancreatitis.
Acute Disease↗
Influence of age, sex and cancer on the activities of gamma-glutamyl transpeptidase and of dipeptidyl aminopeptidase IV in rat tissues.
gamma-Glutamyl transpeptidase (GTP; EC 2.3.2.2) is an enzyme known to show activity changes during development and carcinogenesis. Its activity was measured in the livers and lungs of female and male rats of different ages, in Morris hepatomas and in experimentally induced pancreatic carcinomas. For comparison purposes, the activity of another peptidase, dipeptidyl aminopeptidase IV (DPAP; EC 3.4.14.1), was assayed in the same tissues. GTP activity was high in fetal liver and hepatomas, but low in adult rat liver, with a marked sex difference, 3 times higher in the female than in the male. In the pancreas, however, the activity of the enzyme was high in the adult but low in the fetus and in pancreatic carcinoma. There were no marked developmental changes or sex differences in pulmonary GTP activities. DPAP levels were low in fetal and neonatal liver and lung, they increased rapidly after birth and showed no sex differences in the adult. In Morris hepatomas and in pancreatic tumors the activity of DPAP was significantly lower than in normal adult liver and pancreas. These results suggest that measurements of GTP (and, to a lesser extent, DPAP) are remarkably suitable for the study of neoplastic cells and tissues.
Age Factors↗
Acute hemorrhagic pancreatic necrosis in mice. Induction in male mice treated with estradiol.
Acute hemorrhagic pancreatic necrosis (AHPN) is induced in young female mice fed fo 4 days a choline-deficient diet containing diet 0.5% DL-ethionine (CDE). Contrary to females, male mice do not develop AHPN when fed the same diet. For determination of whether estrogens are involved in the induction of AHPN, estradiol-treated male mice were fed the CDE diet. In such estrogen-treated male mice, the mortality rate, incidence of AHPN, and alterations in biochemical parameters of the pancreas and of serum were similar to those induced by the CDE diet in females.
Acute Disease↗
Stimulation of DNA synthesis and cell proliferation in the liver of rats fed a choline-devoid diet and their suppression by phenobarbital.
Feeding of choline-devoid (CD) diet and dietary administration of phenobarbital (PHB) are efficient promoters of liver carcinogenesis in the rat. Furthermore, inclusion of PHB in a CD diet results in a synergistic effect, inasmuch as the promoting action of their combination is greater than the sum of those exerted by either agent alone. To investigate the mechanism(s) of action of the two promoters, liver DNA synthesis and liver cell proliferation were studied in rats fed a CD diet, a choline-supplemented diet, or the same diets to which 0.06% PHB was added. DNA synthesis was determined by [3H]thymidine incorporation into DNA and autoradiography, and cell proliferation was determined by mitosis counts. Feeding the CD diet caused an increase of both DBA synthesis and cell proliferation over those present in rats fed the choline-supplemented diet. Inclusion of PHB in the CD diet, on the other hand, inhibited DNA synthesis and cell proliferation. These results indicate that stimulation of cell proliferation per se may not be a sufficient condition for an agent to act as a promoter of liver carcinogenesis.
Animals↗
Acute hemorrhagic pancreatic necrosis in mice: alterations of serum complement.
Induction of acute hemorrhagic pancreatic necrosis by dietary means in mice produces alterations in the serum complement system. Total hemolytic complement, i.e., CH50, and native C3 levels fall during the development of pancreatitis while, at the same time, what could be immunoreactive C3 degradation products are demonstrable both in the circulation and in the urine. No evidence of renal deposition of C3 was obtained by immunofluorescence analysis, although marked alterations in proteinuria were observed, suggesting that renal dysfunction(s) is a feature of acute hemorrhagic pancreatic necrosis. Lack of renal complement deposition, together with our earlier negative findings with respect to pancreatic localization, suggests that serum complement alterations are side effects of the pancreatitis, attributable to intravascular, pancreatic enzyme-mediated degradation of serum complement components.
Albuminuria↗
Rapid development of large numbers of alpha-fetoprotein-containing "oval" cells in the liver of rats fed N-2-fluorenylacetamide in a choline-devoid diet.
Fischer rats, fed 0.05% w/w N-2-fluorenylacetamide in a choline-devoid diet for 2 weeks, develop a massive infiltration of the liver by small "oval" cells. This occurs rapidly one week after feeding the diet for two weeks. All rats fed choline-devoid diet die within 5 weeks, with massive oval cell infiltration of the liver. Although similar changes occur in rats fed N-2 fluorenylacetamide in a choline-supplemented diet, their degree is much less. In rats fed a choline-devoid diet without N-2-fluorenylacetamide, proliferation of hepatocytes, but not of oval cells, is observed. Because the carcinogen-enhancing effects of choline-devoid diets seem to exceed those of partial hepatectomy, such diets may work by causing changes distinct from those induced by partial hepatectomy. Many oval cells contain alpha-fetoprotein, and the rapid oval cell increase is associated with an exponential increase in serum alpha-fetoprotein concentration. These observations suggest that a cellular change, not an alteration of gene expression in parenchymal cells, is the primary cause of hyper-alphafetoproteinemia during the course of chemical carcinogenesis in rats.
2-Acetylaminofluorene↗
Isolation of oval cells and transitional cells from the livers of rats fed the carcinogen DL-ethionine.
For the characterization of the metabolic and biologic properties of oval cells (i.e., cells emerging in the livers of rats treated with chemical carcinogens due to proliferation of bile ductular and/or duct cells) and transitional cells (i.e., cells having properties intermediate between those of oval cells and hepatocytes), these cells were isolated from the livers of Sprague-Dawley rats fed DL-ethionine for 4-5 weeks. The livers were dissociated into single cells by perfusion in situ with collagenase, and total cell suspensions were allowed to stand at unit gravity for 10 minutes to separate parenchymal (hepatocytes) from nonparenchymal cells. Nonparenchymal cells were centrifuged in linear gradients of Metrizamide (8-24% wt/vol), and 2-ml fractions were collected from the gradients. The cells in the fractions were defined by light microscopy, electron microscopy, and histochemical and immunofluorescence methods. A cell isolate was thus obtained consisting of Kupffer's cells (approximately 20%), bile ductular and/or duct cells and oval cells (approximately 30%), and transitional cells (approximately 50%). A twofold enrichment of bile ductular and/or duct cells and their derivatives was achieved over that found in the nonparenchymal cell fraction before isopyknic gradient centrifugation.
Animals↗
Segmental action and stimuli-sensitive myoclonus with acute onset. A case report.
A 23-year old man developed action and stimulus-sensitive myoclonus involving neck and proximal arm muscles. The finding of abnormally long and tortuous vertebral and carotid arteries and the abrupt onset of symptomatology suggest a possible hemodynamic mechanism. The electrophysiological characters and the sensitivity to serotonin precursors are consistent with the definition of "reticular reflex myoclonus".
5-Hydroxytryptophan↗
Acute hemorrhagic pancreatic necrosis in mice. Alterations of pancreatic lipase activity, pancreas lipids, and serum lipoproteins.
Acute hemorrhagic pancreatic necrosis (AHPN) with fat necrosis was induced in female mice by feeding a choline-deficient diet containing 0.5% DL-ethionine. Pancreatic lipase increases significantly prior to the onset of AHPN and is not accompanied by gross alterations in the lipid composition of the organs. In the same animals significant activities of pancreatic lipase were detected in serum and peritoneal cavity after 3 days of dietary regimen. Analysis of serum lipids and lipoproteins indicated no hyperlipemia prior to or after onset of AHPN.
Acute Disease↗
Preparation of water-soluble high-molecular weight substrates for beta-D-galactosidase.
Two types of high-molecular water-soluble substrates of beta-D-galactosidase were prepared. Substrate I contains beta-D-[3H]-galactopyranosyl moieties linked, through a hydrocarbon bridge, to a polymeric dialdehyde (oxidized starch) backbone (molecular weight 6,000); in substrate II the backbone is poly-L-lysine (molecular weight 80,000). In the presence of Triton X-100, but not in its absence, D-[3H]-galactose is split from the substrates by homogenates of normal mouse liver or pancreas. It is suggested that substrates I and II could be used to test the integrity of lysosomal and other cellular membranes, and to assess the extent of cellular injury.
Aldehydes↗
Synergistic effect of a choline-devoid diet and phenobarbital in promoting the emergence of foci of gamma-glutamyltranspeptidase-positive hepatocytes in the liver of carcinogen-treated rats.
The effect of feeding phenobarbital (PHB) with a choline-devoid (CD) diet on the emergence of foci of gamma-glutamyltranspeptidase (GGT)-positive hepatocytes in the liver of carcinogen-treated rats was investigated. Male Sprague-Dawley rats were given a single dose of diethylnitrosamine (50 mg/kg) 18 hr after a partial hepatectomy and 10 days later were placed on a plain choline-supplemented (CS) diet, a plain CD diet, or the CS and CD diets containing 0.06% PHB. Groups of rats were killed after 5 and 7 weeks of feeding each of the four diets, the livers were taken, and the number and size of foci of GGT-positive hepatocytes were determined. In rats fed the CS + PHB diet, the number of foci per sq cm of liver section was greater than that in rats fed the plain CS diet but smaller than that in rats fed the plain CD diet. Addition of PHB to the CD diet resulted in twice as many foci as in the plain CD diet and foci larger than those resulting from the plain CD diet. THe hepatocytes in the foci of rats fed th CD and CD + PHB diets showed, uniformly, not only GGT positively but also a relative absence of fatty change. The results indicate that PHB and a CD diet, when combined, have a synergistic effect in promoting the evolution of liver cells, initiated by a chemical carcinogen, to foci of altered GGT-positive hepatocytes. This promoting regimen may become useful in studies concerned with the initiation and promotion stages of liver carcinogenesis.
Animals↗
Acute hemorrhagic pancreatic necrosis in mice: the activity of lysosomal enzymes in the pancreas and the liver.
The activity of lysosomal enzymes of the pancreas and the liver has been studied during induction and onset of acute hemorrhagic pancreatic necrosis with fat necrosis (AHPN) in mice. We induced AHPN by feeding the animals a choline-deficient (CD) diet containing 0.5% DL-ethionine (CDE). Control animals were fed either laboratory chow or a plain CD DIET. Increased total activities of cathespin B1, beta-galactosidase, and acid phosphatase were found to occur in pancreas homogenates of mice fed the CDE diet for 2 and 3 days. Release of cathespin B1 into pancreas cytosol was observed after 1 day of feeding. beta-galactosidase and acid phosphatase were increased in pancreas cytosol after 2 and 3 days of feeding. Changes in total activity and location of the lysosomal enzymes did not occur in the liver. Feeding the CD and CDE diets resulted in an increase in the free activity of lysosomal enzymes of both the pancreas and the liver, suggesting the existence of alterations in the lysosomal membrane. Pancreas and liver homogenates were stored on ice up to 3 hours, and the free activity of acid phosphatase and beta-galactosidase were determined at various time intervals. The free activity of both enzymes increased progressively for 3 hours in the pancreas but not in the liver. It is concluded that: 1) induction of AHPN in mice is accompanied by an increase in the activity of lysosomal enzymes of the acinar cells of the pancreas; 2) cathepsin B1 may be responsible for triggering an intraparenchymal activation of zymogens, and 3) pancreatic lysosomes are labilized more easily than liver lysosomes.
Acid Phosphatase↗
Enhancement of 2-acetylaminofluorene liver carcinogenesis in rats fed a choline-devoid diet.
The effects of feeding a choline-devoid (CD) or a choline-supplemented (CS) diet on the induction of liver tumors in rats by 2-acetylaminofluorene (AAF) were investigated. Male Sprague-Dawley rats were fed either a CD or a CS diet containing 0.0075% AAF. Three to eight animals were killed 1, 3, 4 and 6 months thereafter. Well to moderately well differentiated hepatocellular carcinomas developed in 50% and 75% of rats fed the CD + AAF diet for 4 and 6 months, respectively. Cholangiocarcinomas developed, after 6 months, in 38% of the animals. No tumor developed in rats fed the CS + AAF diet. The results extend to AAF those previously obtained with DL-ethionine and azaserine showing that feeding a CD diet greatly potentiates the induction in rats of liver tumors by chemical carcinogens.
2-Acetylaminofluorene↗
Postinduction bacteremia in experimental acute pancreatitis.
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Acute Disease↗
Induction of foci of altered hepatocytes by a single injection of azaserine to rats.
The induction of foci of altered, gamma-glutamyltranspeptidase (GGT)-positive hepatocytes by azaserine was investigated. After injection of a single dose of azaserine, many foci developed in male Wistar rats fed a choline-devoid (CD) diet containing acetylaminofluorene (AAF), but only a few in rats fed a choline-supplemented (CS) diet containing AAF. Similar results were obtained in rats fed a plain CD diet or a plain CS diet and injected with a single dose of azaserine after a partial hepatectomy. These findings indicate that azaserine is an effective initiator of liver carcinogenesis in rats, and that a CD diet acts as a strong promoter of the evolution initiated liver cells to foci of altered, GGT-positive hepatocytes.
2-Acetylaminofluorene↗
Induction of foci of altered, gamma-glutamyltranspeptidase-positive hepatocytes in carcinogen-treated rats fed a choline-deficient diet.
A series of experiments was performed to investigate whether, after exposure of rats to a chemical hepatocarcinogen, feeding a choline-deficient (CD) diet would promote the proliferation of initiated liver cells, and their evolution to foci of altered γ-glutamyltranspeptidase (GGT)-positive hepatocytes, without subjecting the animals to further experimental manipulations.Diethylnitrosamine (DEN), in single doses of 15-150 mg/kg body weight, was injected into male, Sprague-Dawley rats, either intact or 18 h after a partial hepatectomy (PH). The animals were then fed either a CD or a choline-supplemented (CS) diet for 2-8 weeks. Emergence in the liver of foci of altered, GGT+ hepatocytes was studied by histological and histochemical techniques. Foci, in varying numbers, developed in the liver of all rats fed the CD diet. The number of foci induced was larger when DEN was administered after PH rather than to intact rats. Foci developed in none of the livers of rats fed the CS diet, except in one experiment in which 30 mg DEN/kg body weight was injected after a PH. In all cases, foci of altered, GGT+ hepatocytes were shown to be α-foetoprotein after immunofluorescence staining of liver sections.It is concluded that feeding a CD diet exerts a strong promoting action on the proliferation and further evolution of liver cells initiated by a chemical carcinogen, providing the basis for a new and efficient procedure for the induction of foci of altered hepatocytes in rat liver.
Animals↗