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PubMed1970

Turnover of mammalian phospholipids. Rates of turnover and metabolic heterogeneity in cultured human lymphocytes and in tissues of healthy, starved and vitamin A-deficient rats.

1. Choline- and inositol-labelled phospholipids of human cultured lymphocytes turn over in a biphasic manner; phytohaemagglutinin activation stimulates turnover. 2. Choline-labelled phospholipids of rat liver and kidney, but not of blood, turn over in vivo as fast as those of duodenum, ileum or colon. Turnover in the intestinal tissues is greater in fed than in starved or vitamin A-deficient rats. In each case phosphatidylcholine turns over relatively faster than sphingomyelin or lyso-phosphatidylcholine. 3. It is concluded that phospholipid turnover of the type described is a common feature of viable cells, and that metabolically favourable conditions increase, rather than decrease, turnover.

Animals↗
PubMed1998

Elevated expression and altered pattern of activity of DNA methyltransferase in liver tumors of rats fed methyl-deficient diets.

DNA methyltransferase (MTase) activity in nuclear extracts from neoplastic and preneoplastic livers of rats fed a methyl-deficient diet (MDD) is elevated compared with that seen in the livers of control rats. Nuclear proteins were prepared in the presence of protease inhibitors including trans-epoxy succinyl-L-leucylamido-(4-guanido)butane and were fractionated by isoelectric focusing. In normal, control liver, two distinct MTase fractions were observed. In MDD-induced malignant liver, a third fraction, in addition to the previous two, was also seen. Both the DNA substrate and the cytosine site specificities of the third MTase fraction differ from those of the other two fractions. The distinct MTase activity in liver tumor has significantly more de novo MTase activity than do the MTase fractions of normal, control liver. Thus, normal and neoplastic rat livers differ in DNA MTase fractionation patterns and site specificities. The altered DNA MTase activity observed in rat liver tumors caused by MDDs may be one of the critical factors contributing to cancer formation through abnormal DNA methylation.

Animals↗
PubMedDate not supplied

Psychophysiological diagnostics in alcohol dependency: Fourier analysis of pupillary oscillations and the receptor test for determination of cholinergic deficiency.

Mnestic disturbances in alcoholics may be related to cholinergic deficiency as well as to central nervous system inactivation. After instillation of tropicamide, cholinergic receptors are blocked and pupillary dilatation occurs. It is assumed that the more severe the cognitive deterioration, the wider the pupillary dilatation. Pupillary oscillations reflect central activation. Changes of pupillary diameter after topical instillation of tropicamide and pupillary oscillations were measured in 44 alcohol-dependent patients aged 40-55 years, diagnosed according to the DSM-III-R as severe alcoholics (>7 symptoms), having been abstinent for at least 3 weeks (objectively tested with carbohydrate-deficient transferrin), compared with 18 healthy controls. The pupillary diameter of the left eye was measured eight times within 103 min, as were pupillary oscillations. Using Fourier analysis, the amplitudes of oscillations were measured in five frequency bands and the sum of the frequency bands was calculated. In addition, central activation was measured during a calculation test at 3 and 103 min. The pupillary dilatation of 22% in alcoholics compared to 14% of normal controls after tropicamide raises the question of a cholinergic deficit in alcohol dependence. With regard to basic activation, measured by Fourier analysis of pupillary oscillations, alcoholics demonstrated significantly lower power (sum of the frequency bands) than controls at baseline and at 3, 20, and 40 min (P < 0.01) as well as at 60, 80, 100, and 103 min (P < 0.05). After a cognitive task, a difference between alcoholics and healthy controls was found at 3 min. Alcoholics showed lower basic activation and decreased cognitive activation. By means of cross-validation, a differentiation between alcohol-dependent patients (n = 44 and n = 42 respectively) and normal controls (n = 18) was possible.

Adult↗
PubMed1992

Liver DNA adducts in methyl-deficient rats administered a single dose of aflatoxin B1.

Using an 8 week Solt-Farber protocol with selection pressure (2-acetylaminofluorene/partial hepatectomy) applied during weeks 6 and 7, we have observed that a single oral administration of aflatoxin B1 (AFB1) to Fischer 344 rats on day 1 of the study, followed by a 3 week feeding regimen of either a methyl-deficient (CMD) or a basal (CMS) diet, results in a relative increase in hepatic preneoplastic lesions in CMD diet fed rats. It has previously been shown that a multiple dosing regimen with AFB1, started after 3 weeks of CMD diet, enhances tumor incidence. In the present study, the role of metabolic activation in the induction of preneoplastic lesions, and liver DNA adduct levels after the first dose of AFB1 in the tumorigenesis model have been investigated. AFB1-DNA adducts were determined at 2-168 h following a single non-necrogenic (100 micrograms/kg body wt) or necrogenic (600 micrograms/kg body wt) dose of AFB1 on day 1 or day 21 of a 3 week treatment with a complete basal or CMD diet. In all rats irrespective of dose, dietary treatment or time of AFB1 dosing, the patterns of adduct formation and repair did not change. In rats receiving AFB1 on day 1, total DNA adduct levels between the diet or dose groups were not significantly different, and quantitatively did not correlate with the observed increase in preneoplastic lesions, suggesting a contribution by additional factors in the initiation of these lesions. Administration of AFB1 on day 21, however, resulted in significantly reduced levels of total adducts at both dose levels in CMD diet fed rats compared to controls. Serum biochemistry data suggest that a prolonged exposure to CMD diet may cause pathological and/or biochemical alterations in hepatocytes with a resultant decrease in metabolic activation of AFB1, thus making it difficult to evaluate whether DNA damage is directly related to tumorigenesis.

2-Acetylaminofluorene↗
PubMed1999

[Cholinergic hypothesis and Alzheimer's disease: the place of donepezil (Aricept)].

This presentation has two objectives: 1) presenting the relationships between the clinical symptoms of Alzheimer's disease and cholinergic deficiency, 2) presenting the results obtained with Aricept (proprietary name of donepezil hydrochloride), one of the most recent drugs developed in the context of the cholinergic hypothesis. One of the earliest pathological events in Alzheimer's disease consists in the degeneration of cholinergic neurons in the subcortical regions and, more particularly, in Meynert's nucleus basalis which projects, in a topographically organized manner, to the cortical regions and hippocampus. Some of those regions less affected by the degenerative process nonetheless retain active post-junctional receptors. The disappearance of cholinergic neurons from the nucleus basalis induces disactivation of the cortical and limbic cells and is responsible for the clinical symptoms, such as attention, memory and behavioral disorders. The marketing authorization application for Aricept is based on various studies designed to enable preliminary dose determination and assess efficacy and safety. The first large-scale study designed to evaluate the efficacy of Aricept administered at a daily dosage of 5 to 10 mg was conducted over 14 weeks. The results show a significant improvement in cognitive function in the treatment groups, compared to the placebo groups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of the study and was still very marked 3 weeks post-treatment discontinuation. The results of a second study conducted over 30 weeks were similar to the foregoing results. Compared to placebo, Aricept at a daily dosage of 5 to 10 mg induces a significant improvement in cognitive function and overall function. At week 24, the patients still showed performances that were superior to their baseline performances. In parallel with its cognitive effects, Aricept was also shown to improve the activities of everyday life and alleviate the distress of caregivers directly confronted with the behavioral disorders of patients suffering from Alzheimer's disease.

Aged↗
PubMed1992

How and where does acute pancreatitis begin?

Circumstantial evidence suggests that gallstone-induced pancreatitis is triggered by obstruction of the pancreatic duct. In this report I will review the results of studies conducted during the last decade that have employed the diet-induced, secretagogue-induced, and duct obstruction-induced models of experimental pancreatitis to investigate the early events that lead to the development of acute pancreatitis. In each of these models, digestive enzyme zymogens and the lysosomal hydrolase cathepsin B were found to become colocalized. These observations have led to the hypothesis that intra-acinar cell activation of digestive enzyme zymogens by lysosomal hydrolases may be an important critical event in the development of acute pancreatitis. Recent morphologic studies evaluating the initial 24 hours after ligation of the opossum pancreatic duct indicate that the earliest lesions in this model of hemorrhagic pancreatitis occur in acinar cells.

Acute Disease↗
PubMed1981

Vitamins and cancer prevention: issues and dilemmas.

Vitamins are a class of organic compounds that are components of an adequate diet. They or their derivatives function as coenzymes, cellular antioxidants, and/or regulators of gene expression. Fourteen vitamins are recognized in human nutrition (Vitamins A, D, E, K, B1, B2, B6, B12, C, niacin, folacin, pantothenic acid, biotin, choline), with deficiencies or excesses in intake leading to changes in protein, nucleic acid, carbohydrates, fat and/or mineral metabolism. Thus, the integrity of physiological systems, including those associated with detoxification, cellular repair, immune processes, and neural and endocrine function, depends upon the nutritional and vitamin status of the host. For these reasons, it may be anticipated that the adequacy of the vitamin supply to cells and tissues would affect the development, progress, and outcome of cancers. In this review, the definition and functions of and requirements and recommended allowance for vitamins are discussed briefly before exploring the evidence, largely from studies in experimental animals, that indicates the nature of the link between vitamins and cancer. Although evidence based on studies in animal systems reveals that vitamin intake and status can modulate the outcome of experimental carcinogenesis, the findings are often conflicting and difficult to interpret. Furthermore, it is not yet possible to develop a suitable prediction of the role of the individual vitamins in tumor development. The significance of these observations for human nutrition and cancer prevention, particularly in reference to ascorbic acid (vitamin C), vitamin E, and B-complex vitamins is considered. Vitamin A and retinoid compounds are discussed elsewhere in the symposium. The many popular misconceptions and unsound advice concerning vitamins and health, including "fake" vitamins-pangamic acid ("vitamin B15") and laetrile ("vitamin B17")-are also discussed. On the basis of current evidence, it would be inappropriate to recommend either substantial changes in habitual vitamin intakes, as provided by an adequate, well-balanced diet, or promotion of megavitamin intakes, as a means of reducing risk from cancers in the human population. However, a prudent approach toward diet and food habits, as a means of better optimizing the health consequences of our complex lifestyle is to be recommended.

Advertising↗
PubMed1993

The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage.

Deficiency of choline and methionine produces hepatic steatosis similar to that seen with ethanol, and supplementation with these lipotropes can prevent ethanol-induced fatty liver. These effects are thought to occur through alterations in membrane phospholipid metabolism, but the mechanism whereby this occurs and the precise nature of the changes brought about by ethanol in the interactions of choline and methionine metabolism remain unclear. Through the known effects on hepatic glutathione (which requires as a precursor a product of methionine catabolism), ethanol might affect hepatic one-carbon metabolism, which requires the participation of both methionine and choline in the transfer of methyl groups. This has been investigated with a radiorespirometric technique to assess the in vivo oxidation of the methyl groups of lipotropes and their intermediates in ethnaol- and control-fed rats. Enzyme activities of one-carbon transfer reactions and the hepatic levels of methionine and alpha-aminobutyrate, an end product of methionine catabolism, have been measured. The effect of ethanol feeding on hepatic S-adenosylmethionine and S-adenosylhomocysteine has also been assessed. Ethanol increases the oxidation to carbon dioxide of the methyl group of methionine by a factor of 2.9 (p = 0.002) and produces a 3.6-fold (p = 0.0001) accumulation of alpha-aminobutyrate, indicating a marked increase in methionine catabolism. Hepatic methionine levels are unchanged by ethanol, however, and this may be explained by a dramatic increase in the turnover of the methyl groups of choline and betaine in response to ethanol (times 3.6 and 4.2, respectively, p < 0.003), suggesting greatly increased use of the choline oxidation pathway to remethylate homocysteine through betaine homocysteine methyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury.

The ultrastructural characteristics of liver progenitor cell types of human atypical ductular reactions seen in chronic cholestasis, in regenerating human liver after submassive necrosis, in alcoholic liver disease, and in focal nodular hyperplasia are compared with liver progenitor cell types seen during experimental cholangiocarcinogenesis in hamsters; during hepatocarcinogenesis in rats; and in response to periportal liver injury induced by allyl alcohol in rats. Three types of progenitor cells have been identified in human atypical ductular reactions: type I: primitive, has an oval shape, marginal chromatin, few cellular organelles, rare tonofilaments, and forms desmosomal junctions with adjacent liver cells; type II: bile duct-like, is located within ducts, has few organelles, and forms lateral membrane interdigitations with other duct-like cells; and type III: hepatocyte-like, is located in hepatic cords, forms a bile canaliculus, has tight junctions with other hepatocyte-like cells, prominent mitochondria and rough endoplasmic reticulum, and some have lysosomes and a poorly developed Golgi apparatus. Each type is seen during cholangiocarcinogenesis in hamsters, but the most prominent cell type is type II, duct-like. A more primitive cell type ("type 0 cell"), as well as type I cells, are seen in the intraportal zone of the liver within 1 to 2 days after carcinogen exposure or periportal injury in the rat, but both type II and type III are seen later as the progenitor cells expand into the liver lobule. After allyl alcohol injury, type 0 cells precede the appearance of type I and type III cells, but most of the cells that span the periportal necrotic zone are type III hepatocyte-like cells showing different degrees of hepatocytic differentiation. Some type II cells are also seen, but these are essentially limited to ducts. It is concluded that there is a primitive stem cell type in the liver (type 0) that may differentiate directly into type I and then into type II, duct-like or or type III hepatocyte-like cells. The terms oval cell, transitional hepatocyte, biliary hepatocyte, hepatocyte-like cell, atypical ductular cell, neocholangiole, etc., are used to describe these cells. Although these terms are useful as general descriptive terms for liver precursor cells at the light microscopic level, the cells included in these descriptive categories may be very different from one another biologically and ultrastructurally.

Animals↗
PubMed1979

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↗
PubMed1995

Nutrients, signal transduction and carcinogenesis.

Choline phospholipids play major roles in cellular regulation in addition to their essential function as structural components of membranes and lipoproteins. The unique functions of choline phospholipids as hormones (platelet activating factor, 1-alkyl, 2-acetylphosphatidylcholine, PAF) and sources (phosphatidylcholine, sphingolipids) of second messengers (sphingosine, diacylglycerol, lysophospholipids, arachidonic acid and its metabolites) may explain how dietary choline influences normal physiological processes as well as a diverse group of pathological processes, including carcinogenesis.

Animals↗
PubMed1975

Cytochrome P-450 in the activation and inactivation of carcinogens.

The capacity of isolate mouse liver microsomes to alter the mutagenicity for bacteria of the primary carcinogen N-methyl-N'-nitro-N-nitrosoguanisine (MNNG) and the secondary one dimethylnitrosamine (DMN) was studied. Microsomal activation of DMN and inactivation of MNNG were decreased by protein- and protein-cholinedeficient diets and were increased by pretreatment with microsomal enzyme inducers. The decrease and increase paralleled the content of cytochrome P-450 present in the different microsomal preparations. With human liver microsomes of differing cytochrome P-450 contents similar correlation was obtained, whereas normal rat liver microsomes did not activate or inactivate DMN or MNNG. Oxidative demethylation of DMN by mouse liver microsomes and the activation of DMN to a mutagen followed similar kinetics. Both reactions were inhibited by carbon monoxide and the inhibition was maximally reversed by monochromatic light at 450 nm. These observations indicate that at least some carcinogens are activated or inactivated by the unspecific cytochrome P-450 dependent enzyme system, suggesting that the extent of this biotransformation may be one factor influencing human carcinogenesis.

Animals↗
PubMed1994

MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice.

The effects of acute and chronic administration of MKC-231, a new choline uptake enhancer, and two other nootropic agents, linopiridine (Dup 996) and tetrahydroaminoacridine (THA) on working memory deficits and decreased hippocampal acetylcholine (ACh) content were studied in a delayed non-matching to sample task, using a T-maze, in ethylcholine aziridinium ion (AF64A)-treated mice. Treatment with AF64A (3.5 nmol, i.c.v.) produced memory deficits and decreased hippocampal ACh content. In acute behavioral experiments, MKC-231 and THA had no significant effect on AF64A-induced memory deficits at any doses tested (0.3, 1.0 and 3.0 mg/kg), whereas Dup 996, at a dose of 1.0 mg/kg, significantly improved memory deficits. In chronic experiments, MKC-231 improved memory deficit at all doses tested (0.3, 1.0, or 3.0 mg/kg p.o., once daily for 11 days) and Dup 996 did so only at a dose of 3.0 mg/kg, whereas THA did not improve memory deficit at any doses tested. In acute neurochemical experiments, MKC-231 and THA did not reverse the AF64A-induced hippocampal ACh depletion. Dup 996, however, further decreased hippocampal ACh content compared to that in the AF64A-treated group. In chronic experiments, MKC-231 significantly reversed hippocampal ACh depletion at doses of 0.3 and 1.0 mg/kg, whereas neither Dup 996 nor THA reversed hippocampal ACh depletion at any doses tested. These results indicate that MKC-231 improved the AF64A-induced working memory deficit and hippocampal ACh depletion, probably by recovering reduced high-affinity choline uptake and ACh release.

Acetylcholine↗