Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia.
TR- mutant rats have an autosomal recessive mutation that is expressed as a severely impaired hepatobiliary secretion of organic anions like bilirubin-(di)glucuronide and dibromosulphthalein (DBSP). In this paper, the hepatobiliary transport of glutathione and a glutathione conjugate was studied in normal Wistar rats and TR- rats. It was shown that glutathione is virtually absent from the bile of TR- rats. In the isolated, perfused liver the secretion of glutathione and the glutathione conjugate, dinitrophenyl-glutathione (GS-DNP), from hepatocyte to bile is severely impaired, whereas the sinusoidal secretion from liver to blood is not affected. The secretion of GS-DNP was also studied in isolated hepatocytes. The secretion of GS-DNP from cells isolated from TR- rat liver was significantly slower than from normal hepatocytes. Efflux of GS-DNP was a saturable process with respect to intracellular GS-DNP concentration: Vmax and Km for efflux from TR- cells was 498 nmol/min.g dry wt and 3.3 mM, respectively, as compared with 1514 nmol/min.g dry wt and 0.92 mM in normal hepatocytes. These results suggest that the canalicular transport system for glutathione and glutathione conjugates is severely impaired in TR- rats, whereas sinusoidal efflux is unaffected. Because the defect also comes to expression in isolated hepatocytes, efflux of GS-DNP from normal hepatocytes must predominantly be mediated by the canalicular transport mechanism, which is deficient in TR- rats.
Division of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
R P
RP
Elferink
R
R
Ottenhoff
W
W
Liefting
J
J
de Haan
P L
PL
Jansen
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D004137:Dinitrochlorobenzene / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006933:Hyperbilirubinemia, Hereditary / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013696:Temperature
D000596:Amino Acids; D004137:Dinitrochlorobenzene; D005978:Glutathione