The transport of bile acids in liver cells

Frimmer, M.; Ziegler, K.

doi:10.1016/0304-4157(88)90020-2

Cited by 170 publications

(59 citation statements)

References 194 publications

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“…63 In the liver a carrier named MBAT (multispecific bile acid carrier) was regarded to transport this compound. [64][65][66] This carrier has not yet been cloned but was found to differ from the bile acid transporters. 54,54 It appears that the RL-Mtx-1 corresponds to the MBAT with respect to sodium-dependent bumetanide transport.…”

Section: Discussionmentioning

confidence: 99%

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

Honscha¹,

Dötsch²,

Thomsen³

et al. 2000

Hepatology

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The antifolates methotrexate and trimetrexate are potent inhibitors of the dihydrofolate reductase, an enzyme that delivers by the metabolism of folate and its reduced forms the C1-groups for the synthesis of nucleotides and amino acids. Methotrexate, which has a comparatively moderate toxicity is one of the most important clinically used chemotherapeutics for the treatment of leukemias, such as acute lymphoblastic leukemia of children. It is also used in breast cancer, squamous tumors of the head and neck, lymphomas, and choriocarcinomas. 1,2 Uptake studies of methotrexate and the natural folic acid derivatives in different tumor and normal cells have shown that at least two different carrier systems mediate the uptake of these compounds. The 40 kd folate binding protein has a high affinity for folic acid but a low affinity for reduced folates. [3][4][5][6][7][8][9][10] The corresponding complementary DNAs (cDNAs) as well as genomic clones have been isolated from various sources, 11-19 but a detailed characterization of the transporter function is still missing.Different cDNAs and genomic clones for the reduced folate carrier, which has a high affinity for the reduced folates 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methotrexate, but a low affinity for folate [20][21][22][23][24] have been also isolated from different immortal cell lines 25-31 but the clones were not characterized in detail.The expression and the abundance of the two carriers varied in different tumor and normal cells. From uptake studies it became evident that, first, in some cell systems both transport systems work in tandem 32 whereas two independently operating carrier systems were also described. 33,34 Second, tumor cells differ from normal cells in their transport properties. [35][36][37][38][39] Results from Chello et al. 40 showed, for example, a 30-fold higher affinity for methotrexate in the mouse leukemia cell line L1210 than in freshly isolated murine intestinal cells.Hepatocytes are exceptional with respect to folate transport. In contrast to most other cells, hepatocytes express a separate carrier system for 5-methyltetrahydrofolate, which is different from the reduced folate transporter. 41,42 We recently characterized the uptake of methotrexate into freshly isolated hepatocytes 43 and showed that this chemotherapeutic is taken up by a sodium-dependent active transport system, which is inhibited by the reduced folates, dihydrofolate, and tetrahydrofolate but not by folate itself. Moreover, substrates of two well-known organic anion transport systems in the liver, the Ntcp1 44,45 and the oatp1, 46 like the bile acids taurocholate and cholate as well as xenobiotics such as bromosulfophthalein, the loop diuretic bumetanide, and the mycotoxin ochratoxin A are potent inhibitors of the hepatocellular methotrexate carrier. Because some substrates were Abbreviations: cDNA, complementary DNA; RL-Mtx, rat liver methotrexate transporter; RACE-PCR, rapid amplification of cDNA ends polymerase chain reaction; DMEM, Dulbecco modi...

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Section: Discussionmentioning

confidence: 99%

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

Honscha¹,

Dötsch²,

Thomsen³

et al. 2000

Hepatology

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“…This is not only corroborated by the fact that MC protein adducts can be found in several organs, for example, kidneys, brain, muscle , but also by the pathological and symptological evidence for renal and/or neurological damage in animals and humans (Azevedo et al, 2002;Beasley et al, 2000;Krienitz et al, 2003;Milutinovic et al, 2002;Nobre et al, 1999Nobre et al, , 2001Pennycott et al, 2004). A most likely explanation for the assumption that primarily hepatotoxicity would occur is the fact that it was realised very early on that MCs cannot permeate across cell membranes but are transported actively into hepatocytes via organic anion transporters (Runnegar et al, 1991), for which bile acid salts (cholate and taurocholate) amongst others, are the bnaturalQ substrates (Frimmer and Ziegler, 1988;Meier, 1996;Meier and Stieger, 2002;Meier et al, 1997;Takikawa, 2002). However, these organic anion transporters are not only expressed in the liver but also in the gastrointestinal tract, the kidney and the brain (blood-brain barrier) (Craddock et al, 1998;Hagenbuch and Meier, 2003;Kullak-Ublick et al, 1998;Kusuhara et al, 1999;Nobre et al, 1999).…”

Section: Microcystins: Organ Specificity/distribution and Eliminationmentioning

confidence: 99%

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

Dietrich

Hoeger

2005

Toxicology and Applied Pharmacology

325

185

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This article reviews current scientific knowledge on the toxicity and carcinogenicity of microcystins and compares this to the guidance values proposed for microcystins in water by the World Health Organization, and for blue-green algal food supplements by the Oregon State Department of Health. The basis of the risk assessment underlying these guidance values is viewed as being critical due to overt deficiencies in the data used for its generation: (i) use of one microcystin congener only (microcystin-LR), while the other presently known nearly 80 congeners are largely disregarded, (ii) new knowledge regarding potential neuro and renal toxicity of microcystins in humans and (iii) the inadequacies of assessing realistic microcystin exposures in humans and especially in children via blue-green algal food supplements. In reiterating the state-of-the-art toxicology database on microcystins and in the light of new data on the high degree of toxin contamination of algal food supplements, this review clearly demonstrates the need for improved kinetic data of microcystins in humans and for discussion concerning uncertainty factors, which may result in a lowering of the present guidance values and an increased routine control of water bodies and food supplements for toxin contamination. Similar to the approach taken previously by authorities for dioxin or PCB risk assessment, the use of a toxin equivalent approach to the risk assessment of microcystins is proposed. D

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“…Unless otherwise indicated, hepatocytes were used after 3-4 h of culture in 5% C02/air at 37°C. Freshly isolated and cultured rat hepatocytes were used in our study to avoid the effect of dedifferentiation and subsequent decrease in intrahepatic bile salt uptake that occurs with longer term cultures (25,26).…”

Section: Introductionmentioning

confidence: 99%

Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes.

Patel¹,

Bronk²,

Gores³

1994

J. Clin. Invest.

258

172

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The transport of bile acids in liver cells

Cited by 170 publications

References 194 publications

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes.

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