Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2,4,5-trichlorophenoxyacetic acid in the mouse liver.
The canalicular multispecific organic anion transporter, cMoat, is an ATP-binding-cassette protein expressed in the canalicular domain of hepatocytes. In addition to the transport of endo- and xenobiotics, cMoat has also been proposed to transport GSH into bile, the major driving force of bile-acid-independent bile flow. We have shown previously that the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), a peroxisome-proliferator agent, significantly increases bile-acid-independent bile flow in mice. On this basis, the effect of the herbicide on cMoat gene expression was studied. A 3.6-fold increase in cMoat mRNA levels and a 2.5-fold increase in cMoat protein content were observed in the liver of mice fed on a diet supplemented with 0.125% 2,4,5-T. These effects were due to an increased rate of gene transcription (3.9-fold) and were not associated with peroxisome proliferation. Significant increases in bile flow (2.23+/-0.39 versus 1.13+/-0.15 microl/min per g of liver; P<0.05) and biliary GSH output (7.40+/-3.30 versus 2.65+/-0.34 nmol/min per g of liver; P<0.05) were observed in treated animals. The hepatocellular concentration of total glutathione also increased in hepatocytes of treated mice (10.95+/-0.84 versus 5.12+/-0.47 mM; P<0.05), because of the induction (2.4-fold) of the heavy subunit of the gamma-glutamylcysteine synthetase (GCS-HS) gene. This is the first model of co-induction of cMoat and GCS-HS genes in vivo in the mouse liver, associated with increased glutathione synthesis and biliary glutathione output. Our observations are consistent with the hypothesis that the cMoat transporter plays a crucial role in the secretion of biliary GSH.
Wielandt
A M
AM
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.
Vollrath
V
V
Manzano
M
M
Miranda
S
S
Accatino
L
L
Chianale
J
J
D015085:2,4,5-Trichlorophenoxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D027321:Anion Transport Proteins; D000838:Anions / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D002994:Clofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism*; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D027321:Anion Transport Proteins; D000838:Anions; D002352:Carrier Proteins; D006540:Herbicides; D015085:2,4,5-Trichlorophenoxyacetic Acid; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002994:Clofibrate