Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypolipidemic activity of tiadenol-disulfoxide, the major metabolite of 1,10-bis(hydroxyethylthio)decane (tiadenol, Eulip) in man and in the rat was assessed in various experimental models versus the corresponding activity of tiadenol. Tiadenol-disulfoxide in the normolipidemic rats lowers total serum cholesterol and serum and liver triglycerides in an extent comparable to that of the reference compound. Likewise, it is equally effective as tiadenol in preventing Triton-induced hyperlipidemia and Nath diet induced hypercholesterolemia; in addition tiadenol-disulfoxide is slightly more effective than tiadenol in increasing HDL-cholesterol in hypercholesterolemic rats. At hypolipidemic doses the compound causes no hepatomegaly, no induction of peroxisomal catalase and palmitoyl-CoA oxidase activities, no smooth endoplasmic reticulum proliferation and no induction of microsomal cytochrome P-450 and of cytochrome P-450 dependent enzyme activities: aminopyrine (aminophenazone) N-demethylase, aniline hydroxylase, zoxazolamine hydroxylase and hexobarbital oxidase. At the suprapharmacological dose of 300 mg/kg tiadenol-disulfoxide, if compared to the reference compound, shows a generally lower order of toxicity on these hepatic parameters. Orally administered tiadenol-disulfoxide is well absorbed by the gastrointestinal tract and is eliminated in urine at 45% of the dose in unchanged form, and the remaining being: glucuron-conjugated tiadenol-disulfoxide (10%), S-oxidized metabolites (15%) and sulfoxidized carboxylic metabolites (15%). The compound is well tolerated both in mice and rats. The results of this comparative study demonstrate that: 1. tiadenol-disulfoxide is a substance with promising hypolipidemic properties; 2. tiadenol-disulfoxide is largely responsible for the hypolipidemic activity of tiadenol; 3. hepatomegaly consequent to tiadenol administration is the consequence of the response of the liver cell to the increased functional demand of the mixed function oxidase (MFO) system involved in the metabolism of the drug; 4. peroxisomal enzyme activities induction observed with both drugs at non-pharmacological doses does not play any role in their hypolipidemic action and is not associated with hepatomegaly.
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PMID:Experimental studies on pharmacology, metabolism and toxicology with tiadenol-disulfoxide. Dissociation of lipid lowering effects and the induction of peroxisomal and microsomal drug-metabolizing enzymes. 366 66

Fifteen male mice (C57/Bl6J) were fed the liquid diet "Stardit" supplemented with vitamins together with phenytoin for 8 weeks; experimental animals and controls were pair-fed. After 8 weeks of treatment, the anesthetized animals were perfused with 3.5% glutaraldehyde. Tissue samples of the cerebral cortex (area 3), cerebellum (vermis), thalamus, hypothalamus, and liver were embedded in Araldite. All phenytoin-treated animals displayed a hepatomegaly. Semithin sections and ultrastructural investigations of the cerebellar vermis showed pyknoses of granule cells and an enlargement and swelling of parallel fibers in presynaptic areas in the molecular layer. The swollen axons showed an accumulation of tubular structures which represented proliferated smooth endoplasmic reticulum. Similar tubular structures were observed in hepatocytes of experimental animals. It is proposed that phenytoin caused an induction of the microsomal system of hepatocytes and granule cells which led to a proliferation of the smooth endoplasmic reticulum. The transport of these organelles to the axon terminals of parallel fibers via the axoplasmic flow is assumed to cause a swelling of the presynaptic area. A dying-back process may then lead to pyknosis of granule cells. Chronic phenytoin administration to mice is a new experimental model of neuroaxonal dystrophy.
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PMID:Degeneration of granule cells following chronic phenytoin administration: an electron microscopic investigation of the mouse cerebellum. 394 Aug 80

Liver regeneration was stimulated in male rats with two-thirds of the liver removed by feeding a basal diet supplemented with acetaminophen (0.35-1.5%; weight basis), 2-acetamidophenol (1.0%) and acetophenetidin (1.0%) over a period of 10 days po, but was in the control range with the m-isomer, 3-acetamidophenol (1.0%), N-butyryl-p-aminophenol (1.0%), o-, m- and p-aminophenols (0.50%) and 4-acetamidothiophenol. In fact, the latter inhibited at a level of 0.60%. The operated young or mature female underwent no significant increase in control response with acetaminophen (1-1.5%). However, as with the male, the wet and dry liver weight percentages were markedly increased in the intact female fed acetaminophen (1.0-1.5%) as also with 2-acetamidophenol (1.0%). Liver enlargement occurred in the intact male with acetophenetidin (1.0%) but not with the N-butyryl- and thiophenol derivatives fed at 1.0 and 0.50%, respectively. Hepatic microsomal preparations from the intact and operated series showed no remarkable changes in cytochrome P-450 nor in the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase, with the more polar acetaminophen and the N-butyryl compound but the enzymes were elevated in the group fed acetophenetidin. Inductive effects on microsomal enzymes were further amplified by injection of several animals per group with phenobarbital ip daily at 80 mg/kg for the last 3 days prior to sacrifice. Increases in increments or liver weight percentages ensued over the basal values and as investigated in an intact male series, the enzymes ranged higher than the uninjected controls and with the thiophenol-fed group, exceeded those of the phenobarbital-injected controls.
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PMID:Liver regeneration and hepatic microsomal enzyme induction by acetaminophen and derivatives. 402 13

Cholesterol metabolism has been investigated in a strain of BALB/C mice that carry an autosomal recessive mutation associated with decreased sphingomyelinase and glucocerebrosidase activity and storage of sphingomyelin and glucocerebroside as well as cholesterol in lysosomes (Pentchev, P. G., Gal, A. E., Boothe, A. D., Omodeo-Sale, F., Fouks, J., Neumeyer, B. A., Quirk, J. M., Dawson, G., and Brady, R. O. (1980) Biochim. Biophys. Acta 619, 669-679). When affected animals are placed on a diet high in cholesterol, they develop hepatomegaly associated with an extensive accumulation of unesterified cholesterol in the liver. Cultured skin fibroblasts derived from these mice also manifest a defect in cholesterol esterification although the uptake and intracellular location of exogenous cholesterol is comparable to that of controls. Microsomal fatty acyl-CoA:cholesterol acyltransferase activity was normal or elevated in extracts of tissues from the affected animals. Furthermore, the subcellular distribution and membrane orientation of acyl-CoA:cholesterol acyltransferase appeared normal in microsomal preparations isolated from affected mice. The blockage of esterification of exogenous cholesterol in the presence of normal transferase activity is suggestive of a defect in a component involved in the intracellular disposition of this sterol. The attenuation in tissue levels of sphingomyelinase and glucocerebrosidase and the accumulation of sphingolipids may reflect alterations in lysosomal function resulting from an imbalance of unesterified cholesterol in these organelles.
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PMID:A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol. 632 48

In order to understand the secondary effects of hypolipidaemic agents in human therapy, the authors have studied the inductive properties of four of these drugs, clofibrate, F1379, fenofibrate and probucol, on hepatic drug metabolizing enzymes in the rat. Each hypolipidaemic molecule was administered once a day for five days at doses ranging from 100 to 450 mg/kg/day. All the drugs tested caused hepatomegaly, the effect being particularly marked in the case of F1379 and fenofibrate; on the other hand they decreased the microsomal protein content, especially after F1379 or probucol treatment. Cytochrome P-450 concentration was not greatly affected, with only a 40% increase by clofibrate (dose 200 mg/kg/day) and by F1379 at the lower dose. It is of interest that all the hypolipidaemic agents tested enhanced the activity of epoxide hydrolase with 4, 5 benzo(a)pyrene oxide as the substrate. Except for fenofibrate and probucol at the lower dose, they all strongly increased the activity. The greatest change was effected by F1379 which led to a three to eight-fold increase over the control values. We also measured UDP-glucuronosyltransferase activities using two substrates belonging to group I (4-nitrophenol) and group II (4-hydroxybiphenyl). It appears that the changes in enzyme activity found depended both on the type and the dose of the drug administered and on the chemical structure of the substrate. This study showed that hypolipidaemic drugs which are chemically related to clofibrate could greatly modify the activity of drug metabolizing enzymes and therefore alter the transformation of drugs administered concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative study of four hypolipidaemic agents on the activity of drug-metabolizing enzymes in rat liver microsomes. 643 12

Health conditions were evaluated in 80 electrical workers exposed for many years to polychlorinated biphenyl (PCB) mixtures with a 42% mean chlorine content, who had blood PCB concentrations from 41 to 1319 micrograms/kg. The clinical study was based on personal history data, physical examination, and laboratory tests (red cell and leukocyte count; determination of haemoglobin, packed cell volume, bilirubin, serum protein electrophoretic fractions, pseudocholinesterase, AST, ALT, GGT, and OCT). Fifteen workers were found to have skin diseases--chloracne (4), folliculitis (4), oil dermatitis (1), juvenile acne (1), and dermatitis due to irritative or allergic agents (5). Sixteen workers showed more or less pronounced hepatic involvement, consisting most often of hepatomegaly with an increase in serum GGT, AST, ALT, and OCT values. In two workers bleeding cavernous haemangiomas were discovered, in one case associated with chronic myelocytic leukaemia. All the workers with chloracne were employed on electric capacitor impregnation with PCBs, and no definite association was found between chloracne and blood PCB concentrations. Conversely, a significant positive association was found between the abnormal liver findings and blood PCB concentrations, particularly trichlorobiphenyl blood concentrations. The abnormal hepatic findings observed are similar to those reported in experimental animals given PCBs, and in some workers such findings should probably be considered as clinical signs of hepatic microsomal enzyme induction.
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PMID:Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health effects. 645 Dec 37

This study evaluated the subchronic (14-day) toxicity of selected (0.2, 1.0, and 4.0 mg/kg) daily subcutaneous injections of diethylstilbestrol (DES) in female (C57B1/6 X C3H)F1 mice. Parameters observed included body and organ weights, gross organ morphology, histopathology, clinical chemistry, and hepatic microsomal enzyme activities. The liver, bone marrow, and thymus are major target organs for DES. Liver enlargement, with associated histopathological changes consistent with mild hepatitis, centrolobular necrosis, and sinusoidal changes were observed. Supporting the histological changes were alterations in serum enzyme levels and microsomal enzyme activity. Bone marrow changes included decreases in the number of cells as well as the number of colony forming units per gram stem cells. Toxicity to the thymus was evidenced by decreased thymic weights and lymphocyte depletion. The hepatic and thymic effects were observed at the lowest (0.2 mg/kg) dose. Although all parameters were not assessed for recovery, those that were evaluated returned to control levels by thirty days after treatment.
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PMID:Subchronic toxicology of diethystilbestrol in the mouse. 662 66

It has been shown in experiments on male rats that administration of cordiamine per os in a dose of 73 mg/kg for 45 days provokes hepatomegaly, proliferation of smooth endoplasmic reticulum in hepatocytes, an increase in the microsomal fraction release, rise in the content of cytochrome P450 and in the rate of N-demethylation of ethylmorphine and p-hydroxylation of aniline in liver microsomes. The spectral magnitude of cytochrome P450 binding with aniline and cordiamine does not change under the effect of the latter drug, while interaction of the enzyme with ethylmorphine decreases. The rate of the recovery of the cytochrome P450-ethylmorphine complex increases 3-fold. It is assumed that an increase in the content of cytochrome and in the rate of xenobiotic hydroxylation in microsomes after prolonged administration of cordiamine might be regarded as substrate induction in nature.
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PMID:[Changes in the hydroxylating function and structure of the hepatic endoplasmic reticulum of the rat as affected by long-term kordiamin administration]. 665 65

Significant declines in the non-induced activities of liver microsomal drug-metabolizing enzymes and in the amount of cytochrome P-450 occur between maturity (16 months) and senescence (27 months) in male Fischer 344 rats, whereas there are essentially no differences between very young (1 month) and mature animals. Several hepatic responses to chronic phenobarbital administration also demonstrate marked age-dependent changes. The livers of young and mature animals exhibit: (1) greater hepatomegaly; (2) faster rates of induction and post-induction recovery of microsomal mixed function oxidase enzyme activities and hemoprotein concentration; and (3) higher maximally induced levels of these components in comparison to senescent rats. When considered with information from previous studies, the present data suggest that the age-related decline in liver drug metabolism may be due to qualitative and/or quantitative changes in the structural and/or functional components of the hepatic microsomal mixed function oxidase system.
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PMID:Effects of aging and phenobarbital on the rat liver microsomal drug-metabolizing system. 678 36

1 The effects of the hypolipidaemic agents ICI 53072 and clofibrate on cardiac output and its distribution to the hepatosplanchnic bed were determined by the use of radioactive microspheres in the rat. The effects of these agents on hepatic DNA content were compared with those of phenobarbitone. Also the effects of ICI 53072 on hepatic microsomal enzymes and bile flow were determined together with the effects of phenobarbitone. 2 ICI 53072 and clofibrate both increased liver size and liver blood flow. A daily dose of 25 mg kg-1 ICI 53072 for 5 days increased liver weight by 55% and liver blood flow by 43%, the latter by enhancing the proportion of cardiac output passing to the hepatosplanchnic bed. The increased liver blood flow with clofibrate (480 mg kg-1 daily for 5 days) was the result of greater cardiac output but the change (35%) was half the increase in liver weight. 3 Phenobarbitone (80 mg kg-1 daily for 5 days) produced a fall in DNA content per unit mass of liver but no change in hepatic DNA relative to body weight. ICI 53072 (25 mg kg-1 daily) increased hepatic DNA relative to body weight but by a lesser extent than it increased liver weight as a proportion of body weight; hence DNA content per unit mass of liver decreased. Clofibrate at three dose levels increased hepatic DNA relative to body weight but only one dose significantly decreased DNA content as a proportion of liver weight. 4 Phenobarbitone (80 mg kg-1 daily) increased bile flow whereas ICI 53072 (25 mg kg-1 daily) had no effect. Both treatments increased hepatic cytochrome P450 content and cytochrome c reductase activity. 5 It is concluded that phenobarbitone increases liver size by hepatocyte enlargement rather than cellular proliferation but that the hepatomegaly produced by the hypolipidaemic agents, at least at some doses, is due to a mixture of both processes. 6 It is further concluded that there is no simple relationship between the mechanism of hepatic enlargement resulting from drug treatment and changes in liver blood flow.
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PMID:Comparison of the effects of the hypolipidaemic agents ICI53072 and clofibrate with those of phenobarbitone on liver size, blood flow and DNA content in the rat. 683 62


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