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Biomedical subjects

U Beuers

Publications and source records attributed to U Beuers.

At least 37 records · Page 2Linked to original sources
PubMed1998

Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain.

Dehydroepiandrosterone sulfate (DHEAS) is the major circulating steroid in man. Pharmacologically, it exerts marked neuropsychiatric effects. Since no target receptor has been identified, we investigated whether the organic anion transporting polypeptide (OATP), a multispecific steroid carrier, transports DHEAS. Expression of the human liver OATP in Xenopus laevis oocytes resulted in high-affinity, partially Na+-dependent uptake of [3H]DHEAS (Km: 6.6 micromol/l). DHEAS transport was inhibited by bromosulfophthalein, bile acids, sulfated estrogens and dexamethasone. Northern blot analysis showed widespread expression of OATP in human brain. These data identify OATP as the first known target protein of DHEAS in human liver and brain.

Animals↗
PubMed1998

[Chronic HIV- and chronic HBV infection with hematuria and proteinuria].

HISTORY AND CLINICAL FINDINGS: A medical examination, undertaken in an apparently healthy 30-year-old man because of his occupational exposure to chemicals, revealed haematuria and proteinuria. Physical examination was unremarkable except for oral hair-leukoplakia and swelling of the cervical, supraclavicular, axillary and inguinal lymph nodes. INVESTIGATIONS: Examination of the urine demonstrated selective glomerular proteins (1.5 g/24 h) and dysmorphic erythrocytes. SGOT and SGPT activities were raised (73 and 129 IU/l, respectively). Active hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) infections were demonstrated virologically. The CD4+ count in blood was reduced to 200 cells/microliter. Renal biopsy showed an IgA nephropathy. TREATMENT AND COURSE: Antiretroviral treatment with zidovudine and lamivudine were started. SGOT and SGPT activities and HIV load fell steadily, while CD4+ cell count rose markedly. Renal functions have remained stable during the past 6 months. CONCLUSION: Signs of glomerular damage are not unusual in systemic diseases, tumors or infections (Hepatitis B and HIV in this case) and they may be the first manifestations of the underlying disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Fibrotic entrapment of the small bowel in congenital intestinal lymphangiectasia.

Congenital intestinal lymphangiectasia is a rare protein-losing enteropathy that is characterized by diarrhea and peripheral edema. This report presents a 37-yr-old woman who had suffered from recurrent diarrhea and peripheral edema since her early childhood and who was admitted for severe attacks of abdominal pain. A diagnosis of intestinal lymphangiectasia was made endoscopically, histologically, and radiographically. Laparotomy revealed complete fibrotic entrapment of the small bowel, which caused partial mechanical bowel obstruction. Surgical decortication led to recovery. To the best of our knowledge, this is the first report on fibrotic entrapment of the small bowel in a patient with long lasting intestinal lymphangiectasia.

Adult↗
PubMed1998

[Cholestasis: therapeutic options].

Ursodeoxycholic acid (UDCA) has been shown to be both an effective and well-tolerated treatment of primary biliary cirrhosis, a model chronic cholestatic liver disease. Beneficial effects of UDCA have also been observed in other cholestatic disorders such as primary sclerosing cholangitis, cystic fibrosis, or intrahepatic cholestasis of pregnancy. Liver transplantation is the treatment of choice in end stage chronic cholestatic liver disease. Symptomatic therapeutic concepts include the treatment of cholestasis-associated problems such as pruritus, osteopathy and vitamin deficiency.

Cholagogues and Choleretics↗
PubMed1997

Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene.

The organic anion transporting polypeptide (OATP) of the basolateral hepatocyte membrane mediates multispecific uptake of anionic and other amphipathic substrates from sinusoidal blood plasma. To investigate the mechanisms controlling OATP expression, the 5'-flanking region of the human OATP gene was isolated from a P1-derived artificial chromosome genomic clone. Sequence analysis of the OATP promoter showed a number of consensus binding sites for both ubiquitous and liver-enriched transcription factors. Transfection of HepG2 cells with a series of 5'-deleted promoter-luciferase constructs identified the minimal promoter region within 91 base pairs relative to the transcription initiation site. A putative silencer element was localized in the -662/-440 region. The minimal promoter was also active in Chang liver, Madin-Darby canine kidney, and Chinese hamster ovary cells, indicating that basal promoter function is independent of liver-specific regulatory mechanisms. In transfected HepG2 cells, taurocholate (100 micromol/L) stimulated and triiodothyronine (1 micromol/L) inhibited OATP promoter activity, whereas hydrocortisone, dexamethasone, beta-estradiol, estrone-3-sulfate, and testosterone had no significant effect. Reverse-transcription polymerase chain reaction analysis showed an increase in OATP messenger RNA in the livers of four patients with chronic cholestatic liver disease compared with three noncholestatic controls. The up-regulation of OATP expression by taurocholate could serve to enhance the sinusoidal efflux of toxic intracellular compounds during chronic cholestasis.

Amino Acid Sequence↗
PubMed1997

Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas.

BACKGROUND & AIMS: Chemotherapy of hepatocellular carcinomas is hampered by the insufficient accumulation of cytostatic drugs within the tumor cells. The aim of this study was to evaluate the feasibility of therapeutic strategies using antineoplastic agents coupled to bile acids. METHODS: Expression of the Na(+)-taurocholate-cotransporting polypeptide (NTCP) was analyzed in six hepatocellular carcinomas and in nonmalignant liver tissue. Uptake of the cytostatic drug [3H]-chlorambucil-taurocholate (S2676) was measured in Xenopus laevis oocytes injected with total messenger RNA (mRNA) from the carcinomas or peritumor tissue or with complementary RNA encoding the NTCP or the organic anion-transporting polypeptide (OATP) of human liver. RESULTS: Expression of hepatocellular carcinoma mRNA in oocytes resulted in mainly Na(+)-dependent uptake of chlorambucil-taurocholate. The level of NTCP mRNA in carcinomas amounted to 56% +/- 27% compared with peritumor tissue. Immunofluorescence studies confirmed the expression of NTCP on the surface of hepatocellular carcinoma cells. OATP expression, determined by immunoblotting, was similar in hepatocellular carcinomas and surrounding liver tissue (n = 3). NTCP mediated Na(+)-dependent uptake of chlorambucil-taurocholate (Michaelis constant, 11 mumol/L), whereas OATP mediated Na(+)-independent uptake. CONCLUSIONS: Hepatocellular carcinomas express the Na(+)-dependent bile acid transporter NTCP. Because NTCP mediates high-affinity uptake of chlorambucil-taurocholate, targeting of cytostatic bile acids to hepatocellular carcinomas could become a feasible therapeutic strategy.

Animals↗
PubMed1997

[Increased liver density in computed tomography as a result of anti-arrhythmia therapy with amiodarone].

PURPOSE: To assess whether the hepatic density on CT scans of patients receiving amiodarone therapy differs significantly from the hepatic density of a control group not receiving the drug. METHODS: Hepatic density was assessed by CT in 31 patients receiving amiodarone, 7 receiving short-term (12-14 days), 8 receiving mid-term (20-89 days) and 16 receiving long-term therapy (3-26 months), as well as in a control group of 15 patients. RESULTS: Mean liver density of all patients under amiodarone therapy (77.9 +/- 11.7 HU) was significantly higher (p < 0.005) than in the control group (56.6 +/- 2.8 HU). The smallest increase in density was found in patients with short-term therapy (64.8 +/- 3.4 HU; p < 0.05), the greatest increase in patients with long-term therapy (85.0 +/- 8.9 HU; p < 0.001). CONCLUSION: In patients receiving amiodarone therapy, a significantly increased hepatic density on CT scans is observed. This finding has to be considered as a differential diagnosis to other hepatopathies with increased density of the liver.

Adult↗
PubMed1996

Hepatic levels of bile acids in end-stage chronic cholestatic liver disease.

In chronic cholestatic liver disease hydrophobic and potentially cytotoxic bile acids are assumed to accumulate in the liver. To test this hypothesis we investigated bile acid levels and pattern in livers and serum of patients with, (A) end-stage chronic cholestatic liver disease, and with (B) end-stage cirrhosis of alcoholic/chronic hepatitic origin who underwent liver transplantation. Bile acids were also analyzed in (C) normal liver tissue. Levels of bile acids were 215 +/- 39.1 nmol/g liver (wet weight) in chronic cholestasis and 120 +/- 32.7 and 56.1 +/- 24.2 nmol/g liver in group B and group C (P < 0.01 and P < 0.005), respectively. Cholic acid was the prevailing bile acid in chronic cholestasis (51%) and was elevated eight-fold as compared to group C (P < 0.005). Chenodeoxycholic acid contributed 41% to total bile acids and was elevated four-fold (P < 0.005). Deoxycholic acid contributed only 1.5% to bile acids in chronic cholestasis as compared to 27% in group C (P < 0.01) and was absent in group B. Levels of lithocholic acid tended to be increased in chronic cholestasis as compared to group C and its sulfation was impaired (P < 0.05). The pattern of serum bile acids in chronic cholestasis agreed well with the bile acid pattern in the explanted livers. We conclude that hepatic accumulation of hydrophobic chenodeoxycholic acid and impaired sulfation of lithocholic acid might contribute to tissue degeneration in chronic cholestatic liver disease due to the detergent effects of these bile acids.

Aged↗
PubMed1996

Molecular and functional characterization of bile acid transport in human hepatoblastoma HepG2 cells.

Bile acids are taken up into human liver by Na+-dependent and Na+-independent transport mechanisms. In hepatocarcinogenesis, numerous liver-specific functions are lost and the uptake of organic anions is markedly reduced. We have investigated the molecular and functional derangements of bile acid transport in the human hepatoblastoma cell line HepG2. Uptake of [3H]-taurocholic acid was saturable and entirely Na+ independent, with the kinetic characteristics of the human liver organic anion transporting polypeptide (OATP). OATP, but not the Na+-dependent bile acid transporter (Na+-taurocholate-cotransporting polypeptide [NTCP]), was detectable by reverse-transcription polymerase chain reaction (RT-PCR) analysis of HepG2 RNA. The level of OATP expression in HepG2 cells was determined by Northern blot analysis and was found to be 40% in comparison with normal liver. Transfection of an OATP-derived phosphorothioate (PTO)-antisense oligonucleotide into HepG2 cells resulted in 77% inhibition of temperature-dependent bile acid uptake. Injection of HepG2 messenger RNA (mRNA) into Xenopus laevis oocytes significantly stimulated Na+-independent taurocholate uptake, indicating the expression of a bile acid transport protein. We conclude that bile acid uptake into human hepatoblastoma HepG2 cells is mediated by the multi-specific organic anion transporting polypeptide OATP. Therapeutic strategies employing bile acid-derived cytostatic agents for the treatment of hepatocellular carcinomas may therefore depend upon the expression of the Na+-independent bile acid transporter OATP in hepatic malignancies.

Animals↗
PubMed1996

[MRI of the pancreas: radiologic-pathologic correlation].

The typical MRI features of the most common pancreatic diseases, such as pancreatitis and adenocarcinoma of the pancreas, have been established. However, even in these common pancreatic disorders, MRI correlation with the underlying pathology is limited for clinical reasons. We emphasize MR-pathological correlation of inflammatory and neoplastic pancreatic changes, including pancreatitis, adenocarcinoma, acinar cell carcinoma, rare cystic and solid pancreatic neoplasms, and islet cell tumors. By highlighting the correlation of key pathological features with MR findings, a better understanding of the MR appearance of pancreatic pathology can be provided. In addition, MRI may prove a powerful tool in detection and characterization of pancreatic tumors.

Adenocarcinoma↗
PubMed1996

Assignment of the human organic anion transporting polypeptide (OATP) gene to chromosome 12p12 by fluorescence in situ hybridization.

BACKGROUND/AIMS: The organic anion transporting polypeptide (OATP) of human liver mediates the basolateral hepatocellular uptake of numerous cholephilic anions and steroidal compounds. The aim of this study was to clone the human OATP gene and to map its chromosomal localization by fluorescence in situ hybridization. METHODS: A polymerase chain reaction-amplified fragment of the human OATP gene was used to isolate a genomic OATP clone from a P1-derived artificial chromosome human genomic library. Human metaphase chromosomes were hybridized with digoxigenin-labeled DNA from the genomic OATP clone and incubated in fluoresceinated antidigoxigenin antibodies for in situ detection of specific hybridization signals. RESULTS: Sequence analysis revealed that the isolated P1-derived artificial chromosome clone contained a large portion of the human OATP gene. Fluorescence in situ hybridization of human chromosomes with the genomic OATP clone resulted in the specific labeling of the OATP gene on the short arm of chromosome 12 at band 12p12. CONCLUSIONS: Mapping of a genomic OATP clone to chromosome 12p12 represents a first step towards the molecular characterization of the human OATP gene. While no liver disease has so far been associated with cytogenetic abnormalities of the short arm of chromosome 12, the genomic OATP sequence provides the basis for studies on gene structure and on the tissue-specific regulation of OATP gene expression.

Anion Transport Proteins↗