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PubMed1965

LIVER LIPIDS OF CHOLINE-DEFICIENT RATS.

1. Four-week-old male and female rats were given choline-deficient diets for 2 weeks. Deficient animals gained nearly as much weight as normal controls of the same sex. 2. The amounts of triglyceride and esterified cholesterol in liver lipids were increased threefold or more by the deficiency. The amounts of the major phosphatides and of unesterified cholesterol were unaffected. 3. In males, deficiency significantly increased the proportion of stearic acid in triglycerides, and, in females, the proportion of arachidonic acid was significantly decreased. 4. In the phospholipids of male rats, choline deficiency produced decreases in the amounts of linoleic acid and arachidonic acid and increased the amount of stearic acid. In the phospholipids of female rats, choline deficiency decreased the amount of arachidonic acid and increased that of linoleic acid. 5. The liver phospholipids of normal male rats had higher proportions of palmitic acid and lower proportions of stearic acid than were found in normal females. These sex differences became statistically insignificant in deficient animals.

Animals↗
PubMed1983

The induction of resistant hepatocytes during initiation of liver carcinogenesis with chemicals in rats fed a choline deficient methionine low diet.

Feeding a choline deficient methionine low (CLD) diet for two weeks can substitute for partial hepatectomy in the genesis with benzo[a]pyrene (B[a]P) or 1,2-dimethylhydrazine (1,2-DMH) of resistant hepatocytes that can be selected with dietary 2-acetylaminofluorene plus partial hepatectomy. With single doses of B[a]P or 1,2-DMH during the feeding of the CLD diet for 3 weeks, the number of foci of hepatocytes positive for gamma-glutamyl transferase is approximately the same as with the same dose of each carcinogen given after partial hepatectomy. DL-ethionine was now found to be positive when given as a single dose to animals on the CLD diet. Feeding ethionine for 6 or 12 weeks in a similar choline lipotrope deficient diet also induced a significant increase in foci of enzyme altered hepatocytes. The results indicate that dietary imbalance can have an important influence on initiation of chemical carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed2005

Review of the carcinogenic activity of diethanolamine and evidence of choline deficiency as a plausible mode of action.

Diethanolamine (DEA) is a chemical used widely in a number of industries and is present in many consumer products. Studies by the National Toxicology Program (NTP) have indicated that lifetime dermal exposure to DEA increased the incidence and multiplicity of liver tumors in mice, but not in rats. In addition, DEA was not carcinogenic when tested in the Tg.Ac transgenic mouse model. Short-term genotoxicity tests have yielded negative results. In view of these apparent inconsistencies, we have critically evaluated the NTP studies and other data relevant to assessing the carcinogenic potential of DEA. The available data indicate that DEA induces mouse liver tumors by a non-genotoxic mode of action that involves its ability to cause choline deficiency. The following experimental evidence supports this hypothesis. DEA decreased the hepatic choline metabolites and S-adenosylmethionine levels in mice, similar to those observed in choline-deficient mice. In contrast, DEA had no effect in the rat, a species in which it was not carcinogenic at a maximum tolerated dose level. In addition, a consistent dose-effect relationship had been established between choline deficiency and carcinogenic activity since all DEA dosages that induced tumors in the NTP studies were also shown to cause choline deficiency. DEA decreased phosphatidylcholine synthesis by blocking the cellular uptake of choline in vitro, but these events did not occur in the presence of excess choline. Finally, DEA induced transformation in the Syrian hamster embryo cells, increased S-phase DNA synthesis in mouse hepatocytes, and decreased gap junctional intracellular communication in primary cultured mouse and rat hepatocytes, but all these events were prevented with choline supplementation. Since choline is an essential nutrient in mammals, this mode of action is qualitatively applicable to humans. However, there are marked species differences in susceptibility to choline deficiency, with rats and mice being far more susceptible than other mammalian species including humans. These differences are attributed to quantitative differences in the enzyme kinetics controlling choline metabolism. The fact that DEA was carcinogenic in mice but not in rats also has important implications for human risk assessment. DEA has been shown to be less readily absorbed across rat and human skin than mouse skin. Since a no observed effect level for DEA-induced choline deficiency in mice has been established to be 10 mg/kg/d, this indicates that there is a critical level of DEA that must be attained in order to affect choline homeostasis. The lack of a carcinogenic response in rats suggests that exposure to DEA did not reach this critical level. Since rodents are far more sensitive to choline deficiency than humans, it can be concluded that the hepatocarcinogenic effect of DEA in mice is not predictive of similar susceptibility in humans.

Animals↗
PubMed2003

Periimplant bone healing under experimental hepatic osteodystrophy induced by a choline-deficient diet: a histomorphometric study in rats.

BACKGROUND: Osseointegration and success of an implant involve the interaction of local and systemic factors such as bone metabolic diseases. PURPOSE: The purpose of this study was to evaluate the effect of experimental hepatic osteodystrophy induced by a choline-deficient diet on periimplant bone healing. MATERIALS AND METHODS: Laminar titanium implants were placed in the tibias of five groups of Wistar rats: those with a (1). controlled diet for 15 days; (2). choline-deficient diet for 15 days; (3). controlled diet for 30 days; (4). choline-deficient diet for 30 days; (5). choline-deficient diet for 15 days and a controlled diet for 15 days (refeeding). Body weight and food intake, hematocrit, and hemoglobinemia were evaluated. The animals were killed at 15 or 30 days post implantation. The liver, kidneys, and tibias were resected and fixed in 20% formalin solution. The tibias were radiographed and processed for histomorphometric evaluation of the periimplant bone area. RESULTS: Histologic studies revealed steatosis in the liver but no alterations in the kidneys. Rats fed a choline-deficient diet showed periimplant bone healing with marked qualitative and quantitative alterations. The periimplant bone area was 28% and 75% lower in experimental animals than in controls at 15 and 30 days, respectively. CONCLUSIONS: Liver alterations caused by a choline-deficient diet alter periimplant osteogenesis qualitatively and quantitatively.

Analysis of Variance↗
PubMed2003

Mandibular bone remodeling under a choline-deficient diet: a histomorphometric study in rats.

BACKGROUND: A deficiency of lipotropic factors in the rat induces renal, hepatic, and/or hematic damage. The aim of the present study was to evaluate the effect of a choline-deficient diet and refeeding on mandibular bone remodeling. METHODS: Fifty Wistar rats were divided into 5 groups: group 1 (G1): control diet for 15 days; group 2 (G2): choline-deficient diet for 15 days; group 3 (G3): control diet for 30 days; group 4 (G4): choline-deficient diet for 30 days; and group 5 (G5): choline-deficient diet for 15 days and control diet for 15 days. All animals were sacrificed by ether overdose. The mandibles were resected, radiographed, decalcified, processed, and embedded in paraffin. Bucco-lingually oriented sections were obtained at the level of the interradicular bone of the medial roots of the left first molar, and stained with hematoxylin and eosin (H & E). Bone tissue density and bone remodeling were determined histomorphometrically. Body weight, food intake, hematocrit, and hemoglobinemia were also recorded. RESULTS: Microscopic observation revealed that osteogenesis was lower in rats fed a choline-deficient diet, at both 15 and 30 days, and that this decrease did not revert with a control diet. Histomorphometric evaluation showed 37% and 27% reduction in bone tissue density at 15 and 30 days, respectively, and a 30% decrease in bone formation at 30 days, compared to controls. CONCLUSION: In this experimental model, a choline-deficient diet led to altered bone remodeling as observed by a marked reduction in osteogenesis.

Analysis of Variance↗
PubMed1975

Determination of carnitine turnover in choline-deficient and cold-exposed rats.

Two experimetns were conducted to study the body pool size and turnover rate of carnitine in rats. The turnover of carnitine was determined by injection of a tracer dose of L-[methyl-14C] carnitine. In experiment 1, carnitine body pool size and turnover in rats fed a choline-deficient basal diet were compared with values obtained from rats fed the basal diet supplemented with choline. These rats were maintained at 22degrees. In experiment 2, carnitine body pool size and turnover were determined in cold-exposed (2degrees) rats fed the choline-deficient basal diet. Carnitine body pool sizes of rats maintained 22degrees and fed the choline-deficient basal diet and the choline-supplemented diet were 35.6 and 41.8 mumoles/100 g body weight, respectively. Carnitine body pool size of rats maintained at 2degrees and fed a choline-deficient basal diet were 6.6 and 56.1 days, for rats fed a choline-supplemented diet, 6.7 and 40.2 days, and for rats maintained at 2degrees and fed a choline-deficient diet, 2.9 and 36.4 days, respectively. Carnitine turnover times obtained with DL-[14C]carnitine in our previous study longer than turnover times obtained with DL-[14C]carnitine in our previous study (j. nutr. 104, 782-792). These observations suggest that D-carnitine is not metabolized the same way as L-carnitine, and that D-carnitine is not cleared from the body within 2 days after injection. The results also suggest that carnitine metabolism can be influenced by the amount of choline in the diet and by cold exposure.

Animal Nutritional Physiological Phenomena↗
PubMed1995

Liver biochemical pathology of choline deficiency and of methyl group deficiency: a new orientation and assessment.

New information on the pathologic effects of a choline deficient diet in the rat, in relation to the biochemical events, has led to a new understanding and orientation of the pathogenesis of both acute and chronic consequences in the liver. The biochemical pathology of choline deficiency is quite different than that of methyl group (lipotrope) deficiency. These studies in our laboratory and elsewhere are generating new insights and hypotheses concerning the genesis of hepatocyte necrosis and hepatocellular carcinoma in the rat fed a choline deficient diet.

Animals↗
PubMed1988

Effect of choline-deficiency and methotrexate administration on peroxisomal beta-oxidation, palmitoyl-CoA hydrolase activity and the glutathione content in rat liver.

Hepatic metabolism of long-chain fatty acids was studied in male rats fed a defined choline-deficient (CD) diet with and without choline and after methotrexate (MTX) administration. Peroxisomal beta-oxidation was increased approximately 4-fold in the peroxisome-enriched fraction of CD-fed animals, whereas the catalase activity was increased 1.3-fold. The urate oxidase activity was marginally affected. The CD-fed rats also revealed elevated capacity for hydrolysis of palmitoyl-CoA in the cytosolic fraction (2.0-fold), whereas the microsomal palmitoyl-CoA hydrolase activity was decreased. Notably, the increased peroxisomal beta-oxidation, the catalase activity and palmitoyl-CoA hydrolase activities (the membrane-bounded and cytosolic) were almost fully prevented by adding choline to the CD-diet. Thus, the change in these enzyme activities appears to be a consequence of a choline-deficiency provoked by the CD diet. MTX administration of normal fed rats (ND diet) had no effects on the peroxisomal beta-oxidation, catalase activity and urate oxidase activity. MTX treatment of the ND-fed animals, however, increased the mitochondrial palmitoyl-CoA hydrolase activity and decreased the microsomal enzyme activity. As choline-deficiency and MTX increased the hepatic lipid level, the overall results suggest that fat accumulation is not an 'induction signal' for increased peroxisomal beta-oxidation. The CD diet alone increased the reduced glutathione content in liver, whereas MTX did not significantly change this level. Whether the changes of H2O2-generating peroxisomal oxidation of long-chain fatty acids may be an important step in a chain of events, which eventually results in tumour formation by choline-deficiency, should be considered.

Acyltransferases↗
PubMed1975

Acute hemorrhagic pancreatitis (massive necrosis) with fat necrosis induced in mice by DL-ethionine fed with a choline-deficient diet.

Female, albino mice were fed a choline-deficient diet containing 0.5% DL-ethionine. All animals died within 5 days due to the development of an acute hemorrhagic pancreatis with fat necrosis throughout the peritoneal cavity. The apancreatitis was characterized by a massive necrosis of the exocrine parenchyma with intense hemorrhage and inflammatory reaction of the stroma. The sequence of histologic and ultrastructural alterations occurring in the acinar cells of the pancreas were studied in mice fed the diet for 1, 2, and 3 days. Major findings consited of accumulation of zymogen granules, vacuolation due to foci of cytoplasmic degradation, and alterations in the morphology of the zymogen granules. The pancreatitis appears to be due to intraparenchymal activation of zymogens, resulting from a synergistic action of choline deficiency with the basic toxicity of ethionine toward the acinar cells of the pancreas. The experimental model simulates closely the acute hemorrhagic pancreatitis with fat necrosis occurring in humans and may prove useful for exploring the pathogenesis of this condition.

Acute Disease↗
PubMed2005

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load.

BACKGROUND: Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as occurs in folate deficiency. A parallel pathway exists for methylation of homocysteine, in which choline, by way of betaine, is the methyl donor. OBJECTIVE: Our goal was to determine whether choline deficiency results in a decreased capacity to methylate homocysteine. DESIGN: C57BL/6J mice were fed diets containing 0, 10, or 35 mmol choline/kg diet for 3 wk. We then administered an oral methionine load to the animals and measured plasma homocysteine concentrations. Also, in a pilot study, we examined 8 men who were fed a diet providing 550 mg choline/d per 70 kg body weight for 10 d, followed by a diet providing almost no choline, until the subjects were clinically judged to be choline deficient or for <or=42 d. A methionine load was administered at the end of each dietary phase. RESULTS: Two hours after the methionine load, choline-deficient mice had plasma homocysteine concentrations twice those of choline-fed mice. Four hours after the methionine load, clinically choline-depleted men had plasma homocysteine concentrations that were 35% greater than those in men not choline depleted. CONCLUSION: These results suggest that choline, like folate, plays an important role in the metabolism of homocysteine in humans and that response to a methionine load may be useful when assessing choline nutriture.

Adult↗
PubMed1986

Morphogenesis of septa in hepatic fibrosis induced by choline deficiency in rats. Correlation between ito cells, pericellular fibrosis, and septa.

Examination of hepatic fibrosis induced by choline deficient diet showed the histogenesis of early fibrosis and septa formation. Male rats were fed a choline deficient diet. Groups of three were sacrificed after 1, 2, 3, 6, 8, 12, and 13 weeks. Control groups of three rats were sacrificed after 6, 8, and 12 weeks. All choline deficient rats showed initial steatosis around the portal tracts. The fat droplets were small at first and gave a microvesicular appearance. As they grew, they gathered around the terminal hepatic venule by the 3rd week. Then, reticular fibers developed around the hepatocytes in the centrolobular area and fibroses connected the terminal hepatic venules. The fat droplets became larger and made nodular masses around the portal tract. These compressed the fibroses to the periphery where they formed septa. After 12 weeks, regenerating nodules developed. Electron microscopy showed that fat storing cells helped cause pericellular fibrosis.

Animals↗
PubMed1987

Modulation of calcium by the carcinogenic process in the liver induced by a choline-deficient diet.

A diet devoid of choline and low in methionine (CD), without any added carcinogen, has been shown to induce 100% preneoplastic nodules and more than 50% cancer in the rat liver. Attempts to understand the mechanism by which a CD diet induces liver cell cancer revealed that like chemical carcinogens, a CD diet also appears to cause alterations in DNA, perhaps mediated by free radicals. Indeed, a CD diet induces nuclear lipid peroxidation prior to the changes in DNA. The CD diet induced DNA alterations coupled with continuing liver cell proliferation may account for the induction of initiated hepatocytes by the CD diet. To gain insight into the nature of free radicals generated by the CD diet, experiments were designed to determine whether agents that modulate free radical effects influence the CD diet induced changes in the liver. We investigated the effect of Ca2+ in the modulation of CD diet induced alterations in the liver. The results show that extra Ca2+ when added to the CD diet prevented some of the early changes due to choline deficiency, such as nuclear lipid peroxidation and DNA damage, but had little or no effect on the triglyceride accumulation in the liver. Also, the same CD diet with extra Ca2+, when used as a promoter after initiation by diethylnitrosamine, decreased the number and size of early putative preneoplastic foci and nodules.

Animals↗
PubMed2002

Administration of diethylnitrosamine in the immediate postnatal period coupled with exposure to a choline deficient diet accelerates hepatocarcinogenesis in the rat.

The objectives of this study were to determine if the combination of: i. neonatal administration of diethylnitrosamine and ii. subsequent feeding of a choline deficient diet could accelerate hepatic premalignancy in the rat. The presence and size of premalignant nodules and the activity of the liver cancer enzyme marker g-glutamyltranspeptidase (gGT) were used as indicators of hepatic premalignancy. Three day old Fisher 344 rats were administered sc, saline or diethylnitrosamine (DENA): 100 mg/Kg. These were divided into choline sufficient (CS) and choline deficient (CD) groups with diets introduced to dams. On postnatal day 21 rats were weaned onto CS or CD diets. Rats in choline sufficient saline-injected (CS), choline sufficient DENA-injected (CS+DENA), choline deficient saline-injected (CD) and choline deficient DENA-injected (CD+DENA) groups were assessed on day 86. Livers of CS and CS+DENA rats were normal in appearance. Livers of CD rats were paler; those of CD+DENA rats contained visible, large, tan liver nodules. Identical results were observed in both sexes. Liver gGT activity was low and comparable in rats of CS and CS+DENA groups. Relative to liver homogenate gGT activity in the CS group, liver homogenate gGT was increased in the CD group: 14.5 fold in males and 18 fold in females; and further increased in the CD+DENA group: 78 fold in males and 54 fold in females. Plasma g-glutamyltranspeptidase exhibited the same trends as liver. The CD+DENA group demonstrated the largest increase in activity: 158 fold in males; 199 fold in females over that in the CS group. Male and female rats belonging to CS and CS+DENA groups were euthyroid; those in CD and CD+DENA groups were hypothyroid. Compared to hormone levels in the CS group, in the CD group, decreases in T3 were: 27% in males and 13% in females; decreases in T4 were: 29% in males and 5.6% in females. Compared to hormone levels in the CS groups, in the CD+DENA groups, decreases in T3 were: 25% in males and 18% in males; decreases in T4 were: 31% in males and 25% in females. Plasma glucose levels were comparable in rats of CS and CS+DENA groups. Relative to these levels, plasma glucose levels in rats of CD and CD+DENA groups were decreased 30% in males and females. Plasma transaminase levels were low and comparable in all groups. The protocol developed accelerated hepatocarcinogenesis in the Fischer 344 rat. In CD+DENA male and female rats, it produced, in 86 days, visible, large hyperplastic lesions displaying high levels of gGT and high levels of plasma gGT that are consistent with being at a well developed advanced premalignant stage of hepatocarcinogenesis without any sign of toxicity.

Alanine Transaminase↗
PubMed1996

Brain folates and DNA methylation in rats fed a choline deficient diet or treated with low doses of methotrexate.

In a recent study we have demonstrated that induced changes in several parameters of one-carbon metabolism in livers of rats fed either a choline deficient diet or treated with low doses of methotrexate may be reversed through restoration of an adequate choline diet and discontinuing of methotrexate (MTX) administration. The present study was aimed at comparing these two treatments for their effect on brain: total folate was 0.69 +/- 0.35 nmol/g in the control group and was significantly lower in the other two groups (0.25 +/- 0.06 in the MTX and 0.45 +/- 0.24 nmol/g in the choline deficient groups, p < 0.01). Both treatments were associated with elongations of the glutamate chains of the folate molecules: the proportion of hepta- and octaglutamyl folates increased from 16% to 31% in the MTX treated and to 33% in the choline deficient group, accompanied with concomitant decreases in the concentrations of tetra- and pentaglutamyl folates. MTX could not be detected in brain tissue in contrast to previous observations of significant amounts found in liver. DNA was significantly (p < 0.05) undermethylated in both treated groups compared to controls. Results are discussed on the basis of the possibility that choline deficiency and MTX treatment appear to impair the capacity of tissues, either a peripheral one as liver or a central one as brain, to incorporate folate.

Animals↗