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1. The liver has an important role in the elimination of circulating catecholamines. Adrenaline and noradrenaline are avidly taken up and metabolized by rat hepatocytes, but the nature of the mechanism(s) involved remains partially unknown. 2. The aim of this work was to further characterize the uptake of catecholamines by isolated rat hepatocytes. For that purpose, the effects of a series of chemically unrelated compounds, including substrates/inhibitors of P-glycoprotein, on [3H]-adrenaline removal was investigated. 3. Freshly isolated rat hepatocytes were incubated in Krebs-Henseleit solution at 37 degrees C with 50 nM [3H]-adrenaline for 5 min. Removal of [3H]-adrenaline was calculated as the sum of [3H]-adrenaline present in cells, and its [3H]-metabolites present both in cells and in the incubation medium. Radioactivity was determined by liquid scintillation counting. 4. Verapamil, quinidine, 1-methyl-4-phenylpyridinium, cimetidine, tetraethylammonium, d-tubocurarine, taurocholate, daunomycin and vinblastine (100 microM), progesterone, bilirubin (200 microM), vecuronium (45 microM), and amiloride (1 mM) significantly reduced [3H]-adrenaline removal. On the other hand, cyclosporine A (100 microM) apparently had no effect. The O-methylated metabolite of adrenaline, metanephrine (30 microM), produced a 40% reduction of [3H]-adrenaline removal. 5. Vinblastine and corticosterone produced concentration-dependent decreases of [3H]-adrenaline removal, with IC50 values of 23.3 and 116.0 microM, respectively. 6. In the presence of verapamil (100 microM), desipramine (1 microM) was devoid of significant effect on [3H]-adrenaline removal. Corticosterone (40 microM) produced a further decrease (+/- 50%) on removal of the [3H]-amine. 7. Removal of [3H]-adrenaline by isolated cells did not show pH-dependence since an increase or a decrease in the pH of incubation medium (to 8.2 or 6.2, respectively) caused no alteration of that parameter. 8. In conclusion, [3H]-adrenaline is efficiently removed and subsequently metabolized by isolated rat hepatocytes. The results are compatible with the involvement of multiple mechanisms in the hepatic uptake of this amine including the type I and the type II hepatic transporters for organic cations, uptake2 and P-glycoprotein.
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
December 1996,
British journal of pharmacology,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
November 1993,
Naunyn-Schmiedeberg's archives of pharmacology,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
January 1978,
Journal of nutritional science and vitaminology,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
January 1988,
Environmental and molecular mutagenesis,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
January 2008,
Drug metabolism and disposition: the biological fate of chemicals,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
January 1993,
Biological trace element research,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
January 1984,
Drug metabolism and disposition: the biological fate of chemicals,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
September 1980,
Toxicology and applied pharmacology,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
February 1981,
Biochimica et biophysica acta,
F Martel, and
C Calhau, and
M J Martins, and
I Azevedo
July 1979,
Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.),
