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
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Date
1999
Journal Title
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Publisher
PORTLAND PRESS
Abstract
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 mu l/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.
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Keywords
ABC transporter, bile flow, canalicular transport, gamma-glutamylcysteine synthetase heavy-subunit gene, xenobiotics, GAMMA-GLUTAMYLCYSTEINE SYNTHETASE, HEPATOCYTE CANALICULAR ISOFORM, MULTIDRUG-RESISTANCE PROTEIN, ATP-DEPENDENT TRANSPORT, CMRP/CMOAT GENE, MESSENGER-RNA, MUTANT RATS, MDR2 GENE, EXPRESSION, CONJUGATE