ABSTRACT
Ascorbic acid uptake is a key step in determining the overall bioactivity of this vitamin. Expression of Na-dependent vitamin C transporters (SVCT; SLC23A1 and SLC23A2) during long-term oxidative stress occurring in several chronic liver diseases may determine the antioxidant defence in this organ. In patients with hepatocellular cholestasis, primary biliary cirrhosis, haemochromatosis and non-alcoholic steatohepatitis, using real-time RT-PCR, an enhanced hepatic expression of both SLC23A1 and SLC23A2, but not other organic anions transporters, such as OATP1A2, OATP1B1 and OATP1B3, was found. To further investigate these findings, we used secondary biliary cirrhosis induced in rats by long-term biliary obstruction as a model of chronic liver disease accompanied by oxidative stress because of bile acid accumulation. In control rat liver, expression of Slc23a1 was low at birth, increased progressively up to adulthood and decreased in senescence, whereas expression of Slc23a2 did not change significantly after birth. In 8-week-old rats, immunohistochemistry and confocal microscopy studies revealed the expression in hepatocytes and bile duct cells of mainly Slc23a1, whereas both Slc23a1 and Slc23a2 were expressed in endothelial, stellate and Kupffer cells. In adult rats, when obstructive cholestasis was maintained for 8 weeks, a significant up-regulation of Slc23a2 accompanied by a down-regulation of Slc23a1 was found. In sum, there is a selective cell-type distribution of SVCT in the liver tissue, which, in addition to differential control in the expression of both isoforms, may play a role in the ability of different liver cell types to take up vitamin C under physiological and pathological conditions.
Subject(s)
Liver Diseases/genetics , Liver Diseases/metabolism , Liver/metabolism , Sodium-Coupled Vitamin C Transporters/genetics , Sodium-Coupled Vitamin C Transporters/metabolism , Adult , Aged , Aging/genetics , Aging/metabolism , Animals , Cholestasis/genetics , Chronic Disease , Fatty Liver/genetics , Female , Gene Expression , Hemochromatosis/genetics , Humans , Liver Cirrhosis, Biliary/genetics , Male , Middle Aged , Non-alcoholic Fatty Liver Disease , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tissue DistributionABSTRACT
Hepatitis B reactivation in hepatitis B surface antigen (HBsAg)-negative and anti-HBsAg antibodies-positive patients is an infrequent complication of chemotherapy, usually with fatal evolution. Here we report an HBsAg-negative patient with a myelodysplastic syndrome, who developed hepatitis B reactivation after chemotherapy and evolved favorably after lamivudine treatment, allowing seroconversion.
Subject(s)
Antiviral Agents/therapeutic use , Bone Marrow Transplantation/adverse effects , Hepatitis B Antibodies/blood , Hepatitis B/diagnosis , Hepatitis B/drug therapy , Immunosuppressive Agents/adverse effects , Lamivudine/therapeutic use , Adult , Female , Hepatitis B Surface Antigens/blood , HumansABSTRACT
Drug targeting might help to overcome resistance to chemotherapy. Here we investigated whether colon cancer and polyps do express functional carriers involved in the uptake of cytostatic bile acid derivatives, in this case Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)], which has been reported to be taken up by colon cancer cells "in vitro", efficiently induce apoptosis and overcome resistance to cisplatin. Although at lower levels than in ileum, a detectable expression of ASBT, OATP8/1B3, OCT1 and OSTalpha in colon tissue was found, which was not impaired in colon cancer or polyps. The expression of OATP-A/1A2 and OSTbeta was also found in colon, but this was markedly decreased in neoplastic colon tissue. In contrast, the expression of OATP-C/1B1 was low in colon but significantly enhanced in neoplastic colon tissue. MDR1 and MRP2 were poorly expressed in colon as compared with ileum, whereas MRP3 expression was higher in colon than in ileum. The abundance of mRNA for these ABC proteins was not changed in colon cancer or polyps. When RNA from different tissues was injected to Xenopus laevis oocytes their ability to take up taurocholate and Bamet-UD2 was enhanced (healthy ileum>healthy colon approximately neoplastic colon tissue). In all cases, uptake was lower for taurocholate than for Bamet-UD2, probably due to that ASBT mediates sodium-dependent uptake of both substrates, whereas additional transporters expressed in these tissues can participate in Bamet-UD2 uptake. In conclusion, our results suggest that the use of cytostatic bile acid derivatives might be a good pharmacological strategy for the treatment of colon tumors.
Subject(s)
Bile Acids and Salts/administration & dosage , Colonic Neoplasms/metabolism , Drug Delivery Systems , Membrane Transport Proteins/metabolism , Polyps/metabolism , Animals , Humans , Membrane Transport Proteins/genetics , Organic Anion Transporters, Sodium-Dependent/genetics , Organic Anion Transporters, Sodium-Dependent/metabolism , Organic Anion Transporters, Sodium-Independent/genetics , Organic Anion Transporters, Sodium-Independent/metabolism , Organic Cation Transporter 1/genetics , Organic Cation Transporter 1/metabolism , Organoplatinum Compounds/pharmacology , Solute Carrier Organic Anion Transporter Family Member 1B3 , Symporters/genetics , Symporters/metabolism , Ursodeoxycholic Acid/pharmacology , Xenopus laevisABSTRACT
The relationship between BA (bile acid) secretion (measured by GC-MS) and the expression of genes (measured by reverse transcription real-time PCR) involved in liver BA transport and metabolism was investigated at 20 and 32 weeks during rat hepatocarcinogenesis. A progressive loss of mRNA for transporters (more marked for Ntcp, Bsep and Mrp2 than for Oatp1/Oatp1a1, Oatp2/Oatp1a4 and Oatp4/Oatp1b2) was found. The mRNA levels of Cyp7a1 and the nuclear receptors FXR (farnesoid X receptor), SHP (small heterodimer partner) and FTF (alpha-fetoprotein transcription factor) were not modified, whereas those of Cyp8b1 were enhanced and those of Cyp27 were reduced. Biliary secretion of CA (cholic acid) remained unchanged, whereas that of CDCA (chenodeoxycholic acid) and other non-C(12)-hydroxylated BAs was diminished. The re-appearance of 'flat-BAs' (mainly allo-BAs at 20 weeks and Delta(4)-unsaturated-BAs at 32 weeks) probably reflects the progressive decrease observed in the expression of 3-oxo-Delta(4)-steroid 5beta-reductase, together with the maintenance of steroid 5alpha-reductase type I. A significant correlation between the 5alpha-reductase/5beta-reductase ratio and bile output of 'flat-BAs' was found. In conclusion, during rat hepatocarcinogenesis, the expression of transporters/enzymes responsible for BA homoeostasis is changed due to mechanisms other than those controlled by FXR/SHP/FTF. These modifications result in the re-appearance of 'flat-BAs', together with an increased CA/CDCA ratio in bile.
Subject(s)
Bile Acids and Salts/biosynthesis , Liver Neoplasms/metabolism , Liver/metabolism , Animals , Biological Transport , Cholestanetriol 26-Monooxygenase , Cholestenone 5 alpha-Reductase/genetics , DNA-Binding Proteins/genetics , Gene Expression , Male , Neoplasms, Experimental , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/genetics , Reverse Transcriptase Polymerase Chain Reaction , Steroid 12-alpha-Hydroxylase/genetics , Steroid Hydroxylases/genetics , Transcription Factors/genetics , Transcription, GeneticABSTRACT
No disponible
Subject(s)
Humans , Outcome and Process Assessment, Health Care , Accidents, Traffic , Spain , Wounds and InjuriesABSTRACT
No disponible