Corpus ID: 18821026

Potent bile salt and organic anion inhibition of methotrexate uptake and accumulation in the freshly isolated rat hepatocyte.

@article{Gewirtz1980PotentBS,
  title={Potent bile salt and organic anion inhibition of methotrexate uptake and accumulation in the freshly isolated rat hepatocyte.},
  author={David A. Gewirtz and Joyce K. Randolph and I. David Goldman},
  journal={Cancer research},
  year={1980},
  volume={40 6},
  pages={
          1852-7
        }
}
Abstract Influx of [3H]methotrexate into freshly isolated hepatocytes is mediated by high- and low-affinity processes, both of which are inhibited by the bile salts, cholate, taurocholate, and deoxycholate, and the organic anions, bromosulfophthalein and rose bengal. At 100 µm concentrations, these compounds inhibit 1 µm [3H]methotrexate influx by 70 to 90%. Dixon plots established a similar Ki (∼20 µm) for taurocholate inhibition of the high- and low-affinity influx routes for methotrexate… Expand
Factors controlling the concentrations of methotrexate in cultured hepatic cells.
TLDR
The polyglutamate metabolites of methotrexate are as inhibitory to the target enzyme dihydrofolate reductase as is metotrexate and have a longer half-life within the cells and thus a greater potential for cytotoxicity. Expand
Efflux in isolated hepatocytes as a possible correlate of secretion in vivo: induced exit of the folic acid analog methotrexate, by dibutyryl cyclic AMP or isobutyl methyl xanthine.
TLDR
The observation of the energy dependence of methotrexate efflux induced by dibutyryl cyclic AMP suggests that this may represent the induction of a “secretory” phenomenon in which drug is released into the capillary sinusoid and/or the bile canaliculus when the hepatocyte is in its normal spatial orientation in the liver lobule in , vivo. Expand
Characterization of the bile acid sensitive methotrexate carrier of rat liver cells
TLDR
The results indicate the presence of a bile acid sensitive methotrexate carrier in hepatocytes which is absent in dedifferentiated hepatoma cells. Expand
Activation by reduced glutathione of methotrexate transport into isolated rat liver cells.
TLDR
It is concluded that binding GSH can affect the redox state of the -S-S-/-SH groups of the cellular plasma membrane and that this effect of GSH might demonstrate involvement of theredox state in the control of MTX permeability. Expand
Transport of Folates and Antifolates in Liver
  • D. Horne
  • Biology, Medicine
  • Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine
  • 1993
TLDR
The hepatocyte has separate systems for uptake of the naturally occurring, reduced folates and for the 4-amino-substituted antifolates, which are taken up by the perfused liver and secreted into bile by apparently active processes. Expand
Induction of methotrexate release from rat hepatocytes in suspension by alpha-adrenergic agents: involvement of calcium and metabolic energy.
TLDR
The involvement of calcium in release of methotrexate from the hepatocyte is substantiated by a dose-dependent response to the calcium ionophore, A23187, in the presence of calcium, with a lack of response in the absence of calcium. Expand
Inhibitory effect of bile salts on the enterohepatic circulation of methotrexate in the unanesthetized rat: Inhibition of methotrexate intestinal absorption
TLDR
It is demonstrated that a variety of organic anions inhibit MTX intestinal absorption, including folic acid and 5-methyltetrahydrofolate and the organic anion rose bengal and sulfobormophthalein were also inhibitory to MTX absorption. Expand
Interaction of probenecid with methotrexate transport and release in the isolated rat hepatocyte in suspension.
TLDR
The studies suggest that the inhibition of hepatic methotrexate secretion by probenecid in vivo is likely to be a consequence of interference with hepatic uptake of the antifolate rather than an interaction of probenicid and methotRexate at a hepatic "secretory" site. Expand
Na+ and pH dependence of 5-methyltetrahydrofolic acid and methotrexate transport in freshly isolated hepatocytes.
  • D. Horne
  • Chemistry, Medicine
  • Biochimica et biophysica acta
  • 1990
TLDR
The results suggest the possibility that 5-CH3-H4PteGlu may be cotransported along with H+ ions in hepatocytes, although they do not rule out a 'catalytic coupling' whereby protons interact with the carrier to stimulate substrate flux without concomitant H+ transport. Expand
Increased accumulation of methotrexate by murine tumor cells in vitro in the presence of probenecid which is mediated by a preferential inhibition of efflux.
TLDR
The results have pharmacological implications with respect to the adjuvant use of probenecid or related organic ions during folate analog therapy of human cancer, and the level of intracellular [3H]methotrexate at steady state was markedly increased. Expand
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There are multiple routes for methotrexate transport in the rat hepatocyte that appear to be, at least in part, distinct from the routes for folic acid and the tetrahydrofolate cofactors. Expand
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TLDR
The data suggested that transport of folates is impaired in uremia and raises the possibility that whatever the measured blood folates level in the uremic individual with retained anions, the rate of uptake of folate-dependent tissues which this blood folate level will sustain may be reduced. Expand
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TLDR
The results suggest that more than one Na (probably two) are cosubstrates in the transport of one bile acid molecule and Na exerts a stimulatory effect on the translocation of the bile Acid-carrier complex across the membranes. Expand
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It is indicated that methotrexate transport in the L1210 cell is carrier-mediated and uphill, and the implication of these findings with respect to the development of more effective folic acid antagonists is considered. Expand
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TLDR
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TLDR
Transport of the folate antagonist, amethopterin, from plasma to bile was studied in the isolated rat liver and it is suggested that hepatic uptake and biliary excretion of the drug is an active carrier-mediated process and may be dependent on two separate energy-requiring systems for the uptake and rheumatoid arthritis excretion. Expand
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TLDR
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TLDR
These studies of an inheritable disorder which appears to be identical to the Dubin-Johnson syndrome in man demonstrate that taurocholate excretion requires at least one step in biliary excretion which is not required by other organic anions such as bile pigment, porphyrins, drugs, and dyes. Expand
A functional, active transport system for methotrexate in freshly isolated hepatocytes.
TLDR
Methotrexate transport was studied in isolated rat liver cells and it was suggested that methotrexate is transported in isolated hepatocytes by an active, sodium dependent process. Expand
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TLDR
Evidence is presented which suggests the conclusion that 5-CH3H,PteGlu transport is dependent on the presence of intact disulfide bonds, and that efflux may also be an energy-dependent phenomenon. Expand
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