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

Late onset of symptoms in a 12 1/2-year-old male with ornithine transcarbamylase (OTC) deficiency were associated with unusual histological features in the liver. The patient presented with an acute onset of hyperammonemia and altered mental status after a 2-day prodrome of vomiting and lethargy. Physical examination showed a combative and disoriented male with icteric sclerae but with no fever or hepatomegaly. The plasma ammonia level was 282 microM. Enzyme assays of liver tissue obtained by percutaneous needle biopsy showed OTC activity of approximately 3% of normal; carbamyl phosphate synthetase was normal. Histopathological findings included severe microvesicular centrilobular steatosis. Hepatic architecture and reticulin framework were well preserved. Many hepatocyte nuclei were filled with glycogen. Electron microscopy showed mitochondria that were rounded and expanded with cristae at the edge of the mitochondrial membrane. In contrast to other reports, only slight variations in size and shape were seen. Megamitochondria and intramatrical paracrystalline inclusions were not identified. The cytoplasm contained scattered fat globules, peroxisomes, and dilated smooth endoplasmic reticulum. The prominent mitochondrial abnormalities commonly found in OTC deficiency were notably absent.
 ...
PMID:Histopathological findings in a male with late-onset ornithine transcarbamylase deficiency. 800 87

Although it has been reported that male rats are more responsive than females to peroxisome proliferation induced by clofibrate, these sex differences have been confirmed in young adult rats. Using 4-, 8-, and 12-week-old F344 rats, postnatal change of the sex-dependent response to clofibrate was investigated. These animals were administered 200 mg/kg body wt./day clofibrate by gavage for 7 days. In 4-week-old rats clofibrate-dependent changes (hepatomegaly, induction of hepatic microsomal and peroxisomal enzymes, proliferation of smooth endoplasmic reticulum and peroxisomes of hepatocytes) were slight in both sexes. In 8- and 12-week-old rats clofibrate-induced changes of males were moderate, whereas those of females were slight. These results suggest that the responsiveness of immature rat to clofibrate is weak and in males the susceptibility is gradually strong during postnatal development.
 ...
PMID:Change of the sex-dependent response to clofibrate in F344 rat liver during postnatal development. 865 Jun 96

This report presents new data on mammalian peroxisomes by studying an unusual rodent: the jerboa (Jaculus orientalis). This animal exhibits some unique peroxisomal properties compared to the rat, such as higher cyanide-insensitive palmitoyl-CoA oxidase specific activity, pattern differences in SDS-PAGE peroxisomal proteins as well as in acyl-CoA oxidase immunoblotting. There is also a peculiar response to a peroxisome proliferator, ciprofibrate. With 250 ppm of ciprofibrate in the diet for 2 weeks, we observed a limited liver peroxisome proliferation as well as a palmitoyl-CoA oxidase activity, enzyme content and mRNA increase. However, there was no increase in catalase activity, nor hepatomegaly which are prominent features of peroxisome proliferation in rats treated under the same conditions. The palmitoyl-CoA oxidase activity increase was weak in the kidney and not observed in the heart. Other subcellular organelle marker enzyme activities did not significantly change, especially the mitochondrial D-3-hydroxybutyrate and succinate dehydrogenases, lysosomal acid phosphatase, cytosolic lactate dehydrogenase and the endoplasmic reticulum NADPH-cytochrome c reductase. However, the activity of the liver membrane endoplasmic reticulum linked omega-lauryl hydroxylase (cytochrome P450 IV A1) increases after ciprofibrate treatment. Jerboa also behaves differently compared to the guinea pig after ciprofibrate treatment since the guinea pig has a weak response towards peroxisome proliferators. In conclusion, this first peroxisome study utilizing a different type of rodent as a laboratory animal, reveals that the jerboa shows unique peroxisome properties and responds in a moderate manner to a peroxisome proliferator, ciprofibrate, without leading to any increase in liver mass. This supports the fact that fibrate molecules may have different targets depending upon the species.
 ...
PMID:Properties of peroxisomes from jerboa (Jaculus orientalis). 879 87

Four male and three female marmosets in each group were exposed to air only, 1000 ppm of HCFC 225ca or 5000 ppm of HCFC 225cb, for 6 h per day for 28 consecutive days. HCFC 225ca caused a slight reduction in body weight. HCFC 225cb occasionally caused somnolence during exposure and vomiting on the first day of exposure. Clinical chemistry findings included a mild reduction of triglyceride, cholesterol and phospholipid levels and increased GOT level in the HCFC 225ca exposure group. HCFC 225cb also caused a reduction of triglyceride levels in some animals. HCFC 225ca caused a slight increase of hepatic carnitine palmitoyltransferase (CPT) activity while HCFC 225cb slightly increased cyanide-insensitive palmitoyl CoA beta-oxidation (FAOS) activity. In the HCFC 225cb exposure group, an increase in cytochrome P-450 content was also observed. HCFC 225ca caused a fatty change in the hepatic cells. Increased incidence of lipid droplets in the hepatic cells and myelin-like bodies in hepatic cells, Kupffer's cells and hepatic blood vessels were observed electron microscopically in the HCFC 225ca exposure group. A proliferation of smooth endoplasmic reticulum was observed in the HCFC 225cb exposure group. Decreased peroxisome volume density in the HCFC 225ca group, and increased volume density in the HCFC 225cb exposed females were seen. However, organ weight measurement and histopathological examination did not reveal hepatomegaly or hypertrophy with either substance. Although slight changes were noticed in peroxisome volume density and in some of the peroxisomal enzyme activities, the changes related to peroxisome proliferation with HCFC 225ca and 225cb were minimal in marmosets compared to those seen in rats. Histopathological examination and hormonal analysis did not reveal any abnormalities in the pancreas or testes.
 ...
PMID:Four-week repeated inhalation study of HCFC 225ca and HCFC 225cb in the common marmoset. 933 32

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.
 ...
PMID:Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study. 952 Mar 39

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with other serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drugtreated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.
 ...
PMID:Preclinical toxicological evaluation of sertraline hydrochloride. 1004 42

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.
 ...
PMID:Preclinical toxicological evaluation of sertraline hydrochloride. 959 98

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. Tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control DNA samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated.
 ...
PMID:A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. 1078 35

An unique cytoplasmic inclusion was found in astrocytes of a 2-month-old female baby who showed Leigh-like brain lesions with lactic acidosis, hypoglycemia and hepatomegaly. Although a defective enzyme was not determined, a metabolic disorder was suggested from clinicopathological observations. Symmetrically distributed lesions consisting of marked gliosis and proliferation of capillaries were observed in the basal ganglia, thalami and tegmentum. The astrocytic cytoplasmic inclusion was exclusively found in the cerebral and cerebellar white matter, where myelination was immature. The inclusion was round and eosinophilic, and positive for glial fibrillary acidic protein, vimentin, alphaB-crystallin, S-100 protein and microtubule associated protein 1B, immunohistochemically. An electron microscopic examination revealed an accumulation of intermediate filaments, ribosome and rough endoplasmic reticulum in the inclusion. The characteristic of this inclusion is different from that of other reported inclusions. The inclusion showed positive immunoreaction against CuZn superoxide dismutase, catalase, advanced glycation end-product and 4-hydroxy-2-nonenal antibodies, which suggest that oxidative stress is involved in the genesis of the inclusion.
 ...
PMID:Unique astrocytic inclusion in a 2 month-old baby showing Leigh-like brain lesions with lactic acidosis. 1083 10

The clinical manifestations of type 1 glycogen storage disease (GSD-1) in patients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shared by Hnf1alpha(-/-) mice deficient of a transcriptional activator, hepatocyte nuclear factor 1alpha (HNF1alpha). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose homeostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1alpha(-/-) mice also develop noninsulin-dependent diabetes mellitus caused by defective insulin secretion. In this study, we sought to determine whether there is a molecular link between HNF1alpha deficiency and function of the G6Pase system. Transactivation studies revealed that HNF1alpha is required for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microsomal G6P transport activity are also markedly reduced in Hnf1alpha(-/-) mice as compared with Hnf1alpha(+/+) and Hnf1alpha(+/-) littermates. On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated in Hnf1alpha(-/-) mice, consistent with observations that G6Pase expression is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1alpha-null mice are caused in part by G6PT deficiency and by perturbations of the G6Pase system.
 ...
PMID:A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1alpha-null mice. 1112 25


<< Previous 1 2 3 4 5 6 Next >>