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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A unique organic form of iron (dicyclopentadienyl iron; ferrocene) has been used to further elucidate specific hepatic histopathologic, biochemical, and molecular parameters associated with dietary iron overload. Male C57BL/6Ibg mice fed a diet containing 0.04-0.2% w/w ferrocene for 115 days displayed severe hepatic siderosis of hepatocytes accompanied by a 15-fold induction of nonheme iron content compared to control mice receiving a diet with normal amounts of iron. The ferrocene treatment led to significant increases in hepatocellular necrosis as measured by plasma alanine aminotransferase activity. Histological assessment of hepatic fibrosis revealed mild increases in collagen deposition localized with accumulations of hemosiderin primarily in centrilobular hepatocytes. Hepatic fibrosis was confirmed by measurement of hepatic hydroxyproline content that was increased 4-fold in ferrocene-fed animals compared to control animals not ingesting ferrocene. Hepatic siderosis was accompanied by significant increases in hepatic malondialdehyde content suggesting the ferrocene-induced iron burden initiated lipid peroxidation in vivo. Expression of the heavy-chain isoform of ferritin mRNA and protein measured in liver after ferrocene feeding was increased approximately 8- and 2-fold, respectively, compared to the appropriate controls. These results, using an organic form of iron fed to genetically well-characterized inbred mice, provide new additional insight into the specific molecular and biochemical events that occur in association with histopathologic changes initiated by iron-induced liver injury. These data support the hypothesis that peroxidation of cellular membrane lipids is an important mechanism involved in the toxicity of excess hepatic iron and possibly the initiation of liver fibrogenesis. The results presented here also provide novel in vivo evidence documenting the cellular modulation of ferritin in response to the toxic effects of hepatic iron overloading and iron-mediated oxidative stress.
Exp Mol Pathol 2000 Feb
PMID:Characterization of hepatic iron overload following dietary administration of dicyclopentadienyl iron (Ferrocene) to mice: cellular, biochemical, and molecular aspects. 1064 Apr 49

Allopurinol is widely used and generally well-tolerated. However, when used in patients with renal insufficiency it may have life-threatening toxic effects known as allopurinol hypersensitivity syndrome (AHS). We previously found that allopurinol increased ear swelling and mortality in a DNFB-induced contact hypersensitivity mouse model. In the present study, we investigated the toxic effect of allopurinol on DNFB-sensitized mice in order to clarify the mechanism responsible for the lethal effect of allopurinol. Allopurinol increased plasma GPT and GOT in DNFB-sensitized mice and markedly increased plasma creatinine and BUN. The increase in plasma GPT and GOT was moderate and declined time-dependently. In contrast, the increase in plasma creatinine and BUN was striking and continued until 18 hr after administration of allopurinol at 100 mg/kg/day. Although allopurinol increased GOT and GPT in DNFB-sensitized mice, no effect was observed in non-sensitized mice even at 100 mg/kg/day, indicating that allopurinol essentially has no toxic effect on the liver. A high dose of allopurinol induced renal impairment even in non-sensitized mice. These observations indicate that there is some biological interaction between allopurinol and DNFB, and suggest that allopurinol may modulate or enhance the inflammatory reactions induced by DNFB, and/or that DNFB may cause metabolic changes via inflammation, leading to the enhanced toxicity of allopurinol. In contrast, TEI-6720, a newly synthesized XOD/XDH inhibitor, had almost no effect on DNFB-sensitized mice. TEI-6720 at 1 mg/kg, in terms of hypouricemic effect, appeared to be more potent than allopurinol at 3 mg/kg. Therefore, the nephrotoxic effect of allopurinol observed in the present study may not be related to XOD/XDH inhibitory activity.
Res Commun Mol Pathol Pharmacol 1999
PMID:Nephrotoxic effects of allopurinol in dinitrofluorobenzene-sensitized mice: comparative studies on TEI-6720. 1074 80

The effects of schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, and dimethyl diphenyl bicarboxylate (DDB), a synthetic intermediate of schisandrin C (also a dibenzocyclooctadiene derivative), on hepatic mitochondrial glutathione redox status in control and carbon tetrachloride (CCl4)-intoxicated mice were examined. Treating mice with Sch B or DDB at a daily oral dose of 1 mmol/kg for 3 d did not produce any significant alterations in plasma alanine aminotransferase (ALT) and sorbital dehydrogenase (SDH) activities. CCl4 treatment caused drastic increases in both plasma ALT and SDH activities in mice. Pretreating mice with Sch B or DDB at the same dosage regimen significantly suppressed the CCl4-induced increase in plasma ALT activity, with the inhibitory effect of Sch B being much more potent. Sch B, but not DDB, pretreatment could also decrease the plasma SDH activity in CCl4-intoxicated mice. The lowering of plasma SDH activity, indicative of hepatoprotection against CCl4 toxicity, by Sch B pretreatment was associated with an enhancement in hepatic mitochondrial glutathione redox status as well as an increase in mitochondrial glutathione reductase (mtGRD) activity in both non-CCl4 and CCl4-treated mice. DDB pretreatment, though enhancing both hepatic mitochondrial glutathione redox status and mtGRD activity in control animals, did not produce any beneficial effect in CCl4-treated mice. The difference in hepatoprotective action against CCl4 toxicity between Sch B and DDB may therefore be related to their ability to maintain hepatic mitochondrial glutathione redox status under oxidative stress condition.
Mol Cell Biochem 2000 Feb
PMID:Differential effect of schisandrin B and dimethyl diphenyl bicarboxylate (DDB) on hepatic mitochondrial glutathione redox status in carbon tetrachloride intoxicated mice. 1082 28

Pregnyl (hCG), a preparation of human chorionic gonadotropin, was evaluated for its effects on the endocrinological, biochemical and genotoxic changes in female Swiss albino mice. hCG treatment at different doses (25, 50 and 100 I.U./Kg/day) for 5 days was found to significantly increase the plasma levels of hCG, estradiol and progesterone in a dose-dependent manner, while the concentrations of LH and FSH remained below the detection levels. The plasma levels of ALT, CK-MB, creatinine and urea were significantly decreased, whereas the concentrations of AST were significantly increased. The treatment was found to significantly increase and decrease the hepatic concentrations of MDA and NP-SH respectively. The hepatic levels of proteins and DNA were not affected, but there was a significant increase in the concentrations of RNA. In addition, hCG treatment did not show any effect on the frequency of occurrence of micronuclei, whereas the ratio of PCE/NCE was found to be significantly increased. These results demonstrate that the hCG treatment in mice affected the pituitary-ovarian hormones in a similar pattern to that of humans. The treatment increased oxidative stress in hepatic cells without disturbing the functions of the liver as well as other organs. This finding may be of value concerning the safe use of hCG and may contribute to the overall antioxidant balance in the body.
Res Commun Mol Pathol Pharmacol 1999
PMID:Evaluation of the effects of pregnyl on pituitary-ovarian hormones and biochemical markers of tissue injury in female Swiss albino mice. 1085 Mar 79

Mortality associated with endotoxin shock is likely mediated by Kupffer cells, alveolar macrophages, and circulating neutrophils. Acute dietary glycine prevents mortality and blunts increases in serum tumor necrosis factor-alpha (TNF-alpha) following endotoxin in rats. Furthermore, acute glycine blunts activation of Kupffer cells, alveolar macrophages, and neutrophils by activating a glycine-gated chloride channel. However, in neuronal tissue, glycine rapidly downregulates chloride channel function. Therefore, the long-term effects of a glycine-containing diet on survival following endotoxin shock were investigated. Dietary glycine for 4 wk improved survival after endotoxin but did not improve liver pathology, decrease serum alanine transaminase, or effect TNF-alpha levels compared with animals fed control diet. Interestingly, dietary glycine largely prevented inflammation and injury in the lung following endotoxin. Surprisingly, Kupffer cells from animals fed glycine for 4 wk were no longer inactivated by glycine in vitro; however, isolated alveolar macrophages and neutrophils from the same animals were sensitive to glycine. These data are consistent with the hypothesis that glycine downregulates chloride channels on Kupffer cells but not on alveolar macrophages or neutrophils. Importantly, glycine diet for 4 wk protected against lung inflammation due to endotoxin. Chronic glycine improves survival by unknown mechanisms, but reduction of lung inflammation is likely involved.
Am J Physiol Lung Cell Mol Physiol 2000 Aug
PMID:Dietary glycine blunts lung inflammatory cell influx following acute endotoxin. 1092 63

The interferon-gamma (IFN-gamma) transgenic mouse expresses the exogenous IFN-gamma gene in the liver and develops chronic hepatitis. For the present experiment, four IFN-gamma transgene (+) mice of 48 weeks of age and 16 IFN-gamma transgene (+) mice of 8 weeks of age were used. The four IFN-gamma transgene (+) mice of 48 weeks of age showed significantly elevated plasma alanine aminotransferase (ALT) and expressed the inducible form of nitric oxide synthase (iNOS) mRNA in the liver. Of the 16 IFN-gamma transgene (+) mice of 8 weeks of age, iNOS mRNA was expressed in the livers of three. These three mice exhibited higher plasma ALT levels than the other mice of 8 weeks of age. The present results suggest that iNOS mRNA expression in the liver might be correlated with the progression of hepatitis.
Int J Mol Med 2000 Sep
PMID:Expression of the inducible form of the nitric oxide synthase gene in the livers of mice with chronic hepatitis. 1093 96

Pretreating mice with schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 1 mmol/kg for 3 days protected against menadione-induced hepatic oxidative damage in mice, as evidenced by decreases in plasma alanine aminotransferase activity (78%) and hepatic malondialdehyde level (70%), when compared with the menadione intoxicated control. In order to define the biochemical mechanism involved in the hepatoprotection afforded by Sch B pretreatment, we examined the activity of DT-diaphorase (DTD) in hepatocytes isolated from Sch B pretreated rats. Hepatocytes isolated from Sch B pretreated (a daily dose of 1 mmol/kg for 3 days) rats showed a significant increase (25%) in DTD activity. The increase in DTD activity was associated with the enhanced rate of menadione elimination in the hepatocyte culture. The ensemble of results suggests that the ability of Sch B pretreatment to enhance hepatocellular DTD activity may at least in part be attributed to the protection against menadione hepatotoxicity.
Mol Cell Biochem 2000 May
PMID:Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity. 1093 39

The effect of cytokine-independent hepatitis on cytochrome P450 (CYP) gene expression remains unknown. Treatment of mice with anti-Fas antibodies (150 microg/kg, i.v.) caused elevated plasma alanine aminotransferase activity at 4 and 24 h after treatment. Under normal reverse-transcription polymerase chain reaction (RT-PCR) amplification conditions, no effect of anti-Fas antibody-induced hepatitis on hepatic CYP 2E1 and 3A gene expression was observed. But lower cycle RT-PCR amplification revealed slight suppression of hepatic CYP 2E1 gene expression. The present results showed that cytokine-independent hepatitis induced by anti-Fas anti-bodies had only a minimal effect on the suppression of CYP gene expression in the liver.
Int J Mol Med 2000 Oct
PMID:Minimal effect of cytokine-independent hepatitis induced by anti-Fas antibodies on hepatic cytochrome P450 gene expression in mice. 1099 39

Recent studies have shown that expression levels of the multidrug resistance gene MDR1, which encodes the drug transporter P-glycoprotein, correlate with prognostic outcomes of certain tumor types. These findings suggest that expression of MDR1 may affect tumor behaviors. To address this issue further, we investigated the expression of mdr1a, a human MDR1 homolog, on the development of hepatocellular carcinoma in a transgenic mouse model carrying the liver-targeted expression of human hepatitis-B virus (HBV) surface antigen. The pathogenetic program was compared in HBV mice carrying either mdr1a(+/+) or mdr1a(-/-). We found that the expressions of proliferative activity markers, Ki67 nuclear antigen, and proliferating cell nuclear antigen were elevated in mdr1a(-/-) mice younger than 10 wk in comparison with those in the same age group of wild-type animals. Replication in the hepatic population as determined by bromodeoxyuridine incorporation tended to support observation that mdr1a(-/-) mice exhibited elevated labeling indices in this age group. Moreover, histologic staining and flow-cytometric analysis showed that the mdr1a(-/-) animals exhibited a higher cell population with polyploidy than did the mdr1a(+/+) counterparts of the same age. However, no significant differences in the expression of the liver-injury markers serum alanine transaminase and aspartate transaminase were observed. Although our results showed that absence of mdr1a expression is correlated with modest enhanced proliferative characteristics in the livers at stage before the development of hepatocellular carcinoma, the overall life spans between these two strains of mice were not significantly different. The implication of these findings to the role of P-glycoprotein in tumor development and cancer chemotherapy is discussed.
Mol Carcinog 2000 Oct
PMID:Elevated expression of hepatic proliferative markers during early hepatocarcinogenesis in hepatitis-B virus transgenic mice lacking mdr1a-encoded P-glycoprotein. 1107 7

Previously we reported carbon tetrachloride-induced body weight loss in rats as a new model of wasting disorders. The oral administration of a low dose of carbon tetrachloride to rats reduced the body weight and food intake at 24 h with a minimal effect on plasma alanine aminotransferase activity. Tumor necrosis factor-alpha, and cyclooxygenase-1 and -2 mRNA expression in the brain was not affected by carbon tetrachloride. Zaltoprofen, which is a non-steroidal anti-inflammatory drug, prevented the carbon tetrachloride-induced body weight decrease, without preventing the carbon tetrachloride-induced loss of food intake. The present results suggest the possible application of this drug for the treatment of wasting disorders.
Int J Mol Med 2001 Jan
PMID:Zaltoprofen prevents carbon tetrachloride-induced reduction of body weight in rats. 1111 17


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