Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to the RI (replicative intermediate RNA) and native RF (replicative form RNA), mouse hepatitis virus-infected cells contained six species of RNA intermediates active in transcribing subgenomic mRNA. We have named these transcriptive intermediates (TIs) and native transcriptive forms (TFs) because they are not replicating genome-sized RNA. Based on solubility in high salt solutions, approximately 70% of the replicating and transcribing structures that accumulated in infected cells by 5-6 h post-infection were multi-stranded intermediates, the RI/TIs. The other 30% were in double-stranded structures, the native RF/TFs. These replicating and transcribing structures were separated by velocity sedimentation on sucrose gradients or by gel filtration chromatography on Sepharose 2B and Sephacryl S-1000, and migrated on agarose gels during electrophoresis, according to their size. Digestion with RNase T1 at 1-10 units/microgram RNA resolved RI/TIs into RF/TF cores and left native RF/TFs intact, whereas RNase A at concentrations of 0.02 microgram/microgram RNA or higher degraded both native RF/TFs and RI/TIs. Viral RI/TIs and native RF/TFs bound to magnetic beads containing oligo(dT)(25), suggesting that the poly(A) sequence on the 3' end of the positive strands was longer than any poly(U) on the negative strands. Kinetics of incorporation of [(3)H]uridine showed that both the RI and TIs were transcriptionally active and the labelling of RI/TIs was not the dead-end product of aberrant negative-strand synthesis. Failure originally to find TIs and TF cores was probably due to overdigestion with RNase A.
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PMID:The RNA structures engaged in replication and transcription of the A59 strain of mouse hepatitis virus. 1116 Dec 78

The hepatotropic viruses, measles, and herpesviruses as well as different drugs were repeatedly shown to act presumably as a trigger in patients with autoimmune hepatitis (AI-H). On the other hand, it is known that viral infections stimulate interferon production, which inactivates the cytochrome P-450 enzymes involved in the metabolism of several endogenous substances and exogenous environmental agents. Moreover, it was reported that several cytokines, including interferons, as well as transforming growth factor beta1 and human hepatocyte growth factor, which are abundantly produced and released in the body during infections, also downregulated expression of major cytochrome P-450 and/or other biotransformation enzymes. It seems that all these factors, in addition to individual immune response and the nature and amount of the neoantigen(s) produced, impair the equilibrium of bioactivation and detoxication pathways, thus leading to the development of AI-H in a genetically predisposed person continually exposed to harmful environmental factor(s). Possible increased/decreased density of lysine residues at position D-related human leukocyte antigen locus (DR)beta71 of the antigen-binding groove may affect the eventual steroid-sparing effect of this critical amino acid at the cellular level. In addition, some food additives, such as monosodium glutamate (MSG) and/or aspartame regularly consumed in excessive amounts, may eventually disturb the delicate balance between a positively charged amino acid residue at position DRbeta71 (lysine or arginine) and a negatively charged amino acid residue at position P4 on the antigenic peptide (glutamic acid or aspartic acid). This may favor formation of a salt bridge between these amino acid residues within the hypervariable region 3 on the alpha-helix of the DRbeta polypeptide and facilitate autoantigen presentation and CD4 T-helper cell activation. MSG and aspartate may also depress serum concentrations of growth hormone, which downregulate the activity of several cytochrome P-450 hepatic and other drug-metabolizing enzymes, thus increasing sensitivity to some environmental agents and possibly influencing efficacy of treatment regimens and final outcome of patients with type 1 AI-H.
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PMID:Possible pathomechanism of autoimmune hepatitis. 1252 21

Sodium xylenesulfonate is used as a hydrotrope, an organic compound that increases the ability of water to dissolve other molecules. Sodium xylenesulfonate is a component in a variety of widely used shampoos and liquid household detergents where it can constitute up to 10% of the total solution. Because of its widespread use, the potential for human exposure to sodium xylenesulfonate is great. Male and female F344/N rats and B6C3F1 mice were administered sodium xylenesulfonate in water or 50% ethanol dermally for 17 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells. 17-DAY STUDY IN RATS: Groups of five male and five female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed rats were similar to those of the control groups. Dermal applications of 300 mL of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 10, 30, 90, 260, and 800 mg sodium xylenesulfonate/kg body weight to males and 13, 40, 120, 330, and 1,030 mg/kg to females. Clinical findings generally involved the skin of dosed animals and included tan or brown skin discoloration and crusty white deposits (presumed to be dried chemical) at the site of application. Neither of these observations were considered significant findings. The relative liver weights of 133 and 400 mg/mL male and female rats were significantly greater than those of the control groups, but the absolute liver weights were not increased and the biological significance of the relative differences in liver weight was unclear. In males and females, the few lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration. 17-DAY STUDY IN MICE: Groups of five male and five female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All mice survived to the end of the study. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately, 20, 60, 190, 540, and 1,600 mg sodium xylenesulfonate/kg body weight to males and 26, 80, 220, 680, and 2,000 mg/kg to females. Clinical findings included crusty white deposits (presumed to be dried chemical) at the site of application in two 133 mg/mL males and in all 400 mg/mL males and females. The absolute and relative liver weights of 15 and 44 mg/mL males and 400 mg/mL males and females were significantly greater than those of the control groups, but the biological significance of these differences was unclear. The few skin lesions observed grossly and microscopically in males and females were generally attributed to repeated clipping and were not considered related to chemical administration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. For special hematology and clinical pathology studies, additional groups of 10 male and 10 female rats were administered 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed male and female rats were similar to those of the control groups. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 6, 20, 60, 170, and 500 mg sodium xylenesulfonate/kg body weight to males and 10, 30, 90, 260, and 800 mg/kg to females. The only notable clinical finding was brown discoloration of the skin at the site of application in dosed animals. Hemaation in dosed animals. Hematology and clinical chemistry parameters of dosed groups of males and females were significantly different from those of the controls in several instances, but these differences were sporadic and did not demonstrate a treatment relationship. The absolute and relative liver weights of males receiving 44, 133, or 400 mg/mL were significantly less than those of the control group, but the biological significance of these differences was unclear, and there were no treatment-related histopathologic effects in the liver. There were no significant differences in liver weights in female rats. Minimal hyperplasia of the epidermis at the site of application occurred in both male and female rats in the control group as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was possibly chemical related. 14-Week Study in Mice: Groups of 10 male and 10 female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. There were no chemical-related deaths. The mean body weight gain of the 400 mg/mL males was significantly greater than that of the control group. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 17, 40, 140, 440, and 1,300 mg sodium xylenesulfonate/kg body weight to males and 20, 60, 170, 530, and 1,630 mg/kg to females. There were no clinical findings related to sodium xylenesulfonate administration. Epidermal hyperplasia occurred in one 44 mg/mL female, two 133 mg/mL males, five 400 mg/mL males, and four 400 mg/kg females. Hyperplasia of the epidermis in 400 mg/mL males and females was probably related to chemical administration. Chronic inflammation of the skin occurred primarily in the control groups of males and females. These lesions consisted of mononuclear inflammatory cells in the dermis. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 60, 120, or 240 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were similar to those of the controls throughout the study. In male groups, there were no clinical findings considered treatment related. In females, clinical findings were limited to irritation at the site of application in one control female, four 120 mg/kg females, and two 240 mg/kg females. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Low incidences of hyperplasia of the epidermis at the site of application occurred in males in the 60, 120, and 240 mg/kg groups. Low incidences of hyperplasia of the epidermis at the site of application also occurred in females in the 120 and 240 mg/kg groups, and they occurred with a significant positive trend. Low incidences of hyperplasia of the sebaceous gland occurred in control and 60 mg/kg males and in control, 120 mg/kg, and 240 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 182, 364, or 727 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 to 105 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were generally similar to those of the controls throughout the study; however, the mean body weights of 727 mg/kg females were greater than those of the control group from week 85 to week 97. With the exception of irritation at the site of application in one 364 mg/kg female, there were no clinical findings related to sodium xylenesulfonate administration. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Hyperplasia of the epidermis occurred in control,364 mg/kg, and 727 mg/kg males and in control and dosed females. In male mice, the incidences occurred with a significant positive trend. Focal ulceration occurred in one 727 mg/kg male and in one female in each dose group. In males and females from control and dosed groups, the incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepato- cellular adenoma or carcinoma (combined) were generally higher than those expected by spontaneous occurrence. The incidences of hepatocellular neoplasms in some groups of males and females exceeded the NTP historical control range. Male mice had a pattern of nonneoplastic liver lesions along with silver stained positive helical organisms within the liver which suggests an infection with Helicobacter hepaticus. The findings in this study of sodium xylenesulfonate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Sodium xylenesulfonate was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced liver S9. Equivocal results were obtained in a mutation assay with mouse lymphoma cells in the presence of induced S9; no evidence of mutagenicity was noted without S9 in this assay. In cytogenetic tests with sodium xylenesulfonate in cultured Chinese hamster ovary cells, significant increases in sister chromatid exchanges were observed in the absence of S9 only, and no increases in chromosomal aberrations were observed with or without S9. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of sodium xylenesulfonate in male or female F344/N rats administered 60, 120, or 240 mg/kg or in male or female B6C3F1 mice administered 182, 364, or 727 mg/kg. Increased incidences of epidermal hyperplasia in female rats and male mice may have been related to exposure to sodium xylenesulfonate. Synonyms: Benzenesulfonic acid, dimethyl-, sodium salt; xylenesulfonic acid, sodium salt; sodium dimethylbenzenesulfonate; xylenesulfonic acid, sodium salt Trade names: Conco SXS; Cyclophil; SXS 30; Eletesol SX 30; Naxonate; Naxonate G; Richonate SXS; Stepanate SXS; Stepanate X; SXS 40; Ultrawet 40SX
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PMID:NTP Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate (CAS No. 1300-72-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies). 1257

Cobalt sulfate is used in the electroplating and electro chemical industries. It is also used as a coloring agent for ceramics and as a drying agent in inks, paints, varnishes, and linoleum. Cobalt sulfate may be added to animal feed as a mineral supplement and has been used as a top dressing on pasture lands. Cobalt sulfate was nominated by the National Cancer Institute for study based on a lack of information on the toxicity of soluble salts. Male and female F344/N rats and B6C3F1 mice were exposed to cobalt sulfate heptahydrate (approximately 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. The results of prechronic inhalation toxicity studies were reported previously (Bucher et al., 1990; NTP, 1991). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Pathology Findings The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of male and female rats than in the chamber controls. The incidences of alveolar epithelial hyperplasia in all groups of exposed males and in females exposed to 3.0 mg/m3 were significantly greater than those in the chamber control groups, as were the incidences of squamous metaplasia in 1.0 mg/m3 females and atypical alveolar epithelial hyperplasia in 3.0 mg/m3 females. In 3.0 mg/m3 males, the combined incidence of alveolar/ bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater than in the chamber controls. In female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were significantly greater than those in the chamber control group and exceeded the NTP historical control ranges. A squamous cell carcinoma was observed in one 1.0 mg/m3 and one 3.0 mg/m3 female. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m3 males and in 3.0 mg/m3 females were significantly greater than those in the chamber controls and exceeded the historical control ranges. Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of males and females, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 males and females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of 3.0 mg/m3 male mice were less than those of the chamber controls from week 96 until the end of the study. The mean body weights of all exposed groups of female mice were generally greater than those of the chamber controls from week 20 until the end of the study. Pathology Findings The incidences of diffuse histiocytic cell infiltration in 3.0 mg/m3 males and of focal histiocytic cell infil tration in 3.0 mg/m3 females were significantly greater than those in the chamber controls. The incidences of alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were significantly greater than those in the chamber control groups. The combined incidences of alveolar/bronchiolar adenoma or carcinoma and the incidences of alveolar/bronchiolar carcinoma in 3.0 mg/m3 males and females and the incidence of alveolar/bronchiolar adenoma in 3.0 mg/m3 females exceeded the NTP historical crical control ranges for inhalation studies. The incidences of atrophy of the olfactory epithelium in 1.0 and 3.0 mg/m3 males and females and hyper plasia of the olfactory epithelium in 3.0 mg/m3 males and females were significantly greater than in the chamber controls. Squamous metaplasia of the larynx was observed in all exposed groups of males and females. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver, characteristic of an infection with Helico bacter hepaticus. In NTP studies with H. hepaticus- associated hepatitis, increased incidences of hemangiosarcoma were seen in the liver of male mice. In this study of cobalt sulfate heptahydrate, incidences of hemangiosarcoma were increased in exposed groups of male mice. Because of the above association, interpretation of the increased incidences of hemangiosarcoma in the livers of male mice was confounded. Incidences of lesions at other sites in this study of cobalt sulfate heptahydrate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Cobalt sulfate heptahydrate was mutagenic in S. typhimurium strain TA100 with and without liver S9 metabolic activation enzymes; no mutagenic activity was detected in strain TA98 or TA1535, with or without S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neo-plasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats and mice. Synonyms: Bieberite; cobalt(II) sulfate (1:1) heptahydrate; cobalt monosulfate heptahydrate; cobalt(II) sulphate heptahydrate; sulfuric acid, cobalt(2+) salt (1:1) heptahydrate
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PMID:NTP Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate (CAS No. 10026-24-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 2

Hepatotoxicity, predominantly cholestatic, is a rare adverse effect of gold salt therapy, which usually completely resolves within a few months. We report the case of a female patient treated for rheumatoid arthritis, who had gold salt overdose, and in whom acute cholestatic hepatitis occurred three weeks after beginning of therapy. Evolution of gold concentration was followed in plasma and urine, as well as in cutaneous and liver dry tissue. Liver biopsy showed marked inflammatory changes of interlobular bile ducts that evolved towards ductopenia, which was responsible for prolonged cholestasis still present 15 months later. In addition, sialadenitis with sicca syndrome was noted six months after onset of the disease. The mechanism of hepatotoxicity was probably immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia. This is the first report of gold salt hepatotoxicity with histological demonstration of cholangitis followed by ductopenia.
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PMID:Prolonged cholestasis and ductopenia following gold salt therapy. 1265 30

Bacteria respond to increasing medium osmolality by accumulating organic solutes that are compatible with cellular functions. Transporter ProP of Escherichia coli, a proton symporter and a member of the major facilitator superfamily, senses osmotic shifts and responds by importing osmolytes such as glycine betaine. ProP contains a cytoplasmic, C-terminal extension that is essential for its activity. A peptide corresponding to the C-terminal extension of ProP forms a homodimeric alpha-helical coiled-coil even though some of its heptad a positions are not occupied by hydrophobic amino acid residues. Unexpectedly, amino acid replacement R488I, occurring at a heptad a position, destabilized the coiled-coil formed by the ProP peptide and attenuated the response of the intact transporter to osmotic upshifts in vivo. Thus, ProP was proposed to dimerize via an antiparallel coiled-coil. We used nuclear magnetic resonance (NMR) spectroscopy to determine the structure of the synthetic peptide corresponding to residues 468-497 of ProP. This region did form an antiparallel coil-coil in which critical residue R488 specifies the antiparallel coiled-coil orientation by forming stabilizing salt-bridges. Charged residues (both acidic and basic) are clustered on the c/g surface of the coiled-coil whereas polar residues are distributed on the b/e surface. This causes the structure to be bent, in contrast to other known antiparallel coiled-coils (those from the hepatitis delta antigen (PDB ID code 1A92) and the bovine F(1) ATPase inhibitor protein (PDB ID code 1HF9)). The coiled-coil and its possible importance for osmosensing are discussed.
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PMID:Solution structure of the C-terminal antiparallel coiled-coil domain from Escherichia coli osmosensor ProP. 1464 66

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR-Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR-Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR-Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR-Abcb11 mice have 3-fold increases in TNF-alpha mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-alpha, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis.
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PMID:Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet. 1565 Jan 32

Technologic advances using cDNA microarray hybridization, liver diseases characterized by mitochondrial DNA depletion, and new work characterizing bile salt transport problems in familial intrahepatic cholestasis syndromes were some of the major highlights of this past year. Analysis of normal livers by cDNA microarrays disclosed 2418 unique gene transcripts encoding a host of cellular structural and functional proteins. This technique was also applied to hepatocellular carcinoma, where enhanced expression of a number of genes involved in antiapoptosis and cell transformation may shed additional light on the process of hepatocarcinogenesis. Mitochondrial DNA depletion seen in Navajo neurohepatopathy and in respiratory chain disorders of infancy was associated with cholestasis and cirrhosis in the former and microvesicular steatosis and oncocytic transformation (mitochondrial hyperplasia) in the latter. Pathologists who routinely examine liver biopsies after liver or bone marrow transplantation should be aware of unusual biopsy features that mimic other diseases, such as the autoimmune hepatitis-like syndrome that may follow liver transplantation and chronic graft-versus-host disease that clinically and pathologically resembles acute hepatitis.
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PMID:Hepatobiliary pathology. 1703 99

The non-steroidal antiandrogen flutamide is widely used for treatment of prostatic cancer, but causes side effects, including cholestatic hepatitis and fulminant hepatitis. We investigated the pathogenesis of flutamide-induced cholestatic hepatitis, focusing on the bile salt export pump (BSEP; ABCB11), which exports bile salts to the bile. We examined the inhibitory effects of flutamide and its active metabolite, hydroxyflutamide, on the transport of taurocholic acid (TCA) by membrane vesicles derived from hBSEP-expressing Sf9 cells. Flutamide inhibited the transport of TCA by hBSEP (IC50 value, about 50 microM), while hydroxyflutamide had no effect at up to 100 microM. When flutamide was administered to rats as a single oral dose of 100 mg/kg, the biliary excretion rate of bolus-injected [3H]TCA was decreased and the liver tissue concentration of flutamide exceeded 50 microM. Repeated doses of flutamide for 5 d (10 mg/kg/d) also decreased the biliary excretion rate of bolus-injected [3H]TCA. In this case, the liver tissue concentration of flutamide was below 0.1 microM. In both cases, no change in the mRNA level of rat Bsep was detected by RT-PCR. These results suggest that flutamide itself, but not its major metabolite, may cause cholestasis by inhibiting BSEP-mediated bile salt excretion.
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PMID:Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis. 1740 13

Suaeda asparagoides Miq. (Chenopodiaceae: S. asparagoides) is a salt-marsh plant that has long been prescribed in traditional Oriental medicine for the treatment of hypertension and hepatitis. In order to elucidate the pharmacological mechanisms of the herb, we conducted an examination of the anti-oxidative and anti-inflammatory properties of solvent-extracts of S. asparagoides. All of the solvent fractions showed potent anti-oxidative effects, as assessed using a radical generation assay system (xanthine oxidase assay) and an electron-donating activity system (DPPH [2,2-diphenyl-l-picrylhydrazyl radical] assay), with IC50 values ranging from 9 to 42 microg/ml. In agreement with this pattern, the total phenolic contents were widely distributed in the various solvent fractions, and ranged from 36.5 to 50.3 mg/g of dry weight. All of the solvent fractions significantly suppressed NO production in RAW264.7 cells induced by lipopolysaccharide (LPS, 0.1 microg/ml) and of the fractions, only the chloroform (CHC) fraction completely blocked the expression of inducible NO synthase (iNOS). Additionally, the hexane (HEX) and CHC fractions suppressed the mRNA expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) and monocyte chemoattractant protein 1 (MCP-1), respectively, in the LPS-stimulated RAW264.7 cells. Therefore, these results suggest that the pharmacological action of S. asparagoides is due to its potent anti-oxidative effects and anti-inflammatory effects, and that therefore it can be applied to other diseases caused by oxidative stress and inflammation, such as cardiovascular diseases.
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PMID:In vitro anti-oxidative and anti-inflammatory effects of solvent-extracted fractions from Suaeda asparagoides. 1766 94


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