Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver.

Background: In mice, fibrates induce mdr2 gene expression, and its encoded P-glycoprotein in the canalicular domain of hepatocytes, as well as increasing biliary phospholipid output. It is not known whether this effect is restricted to fibrates or is a common property of peroxisome proliferators.

Aims: To test the effect of structurally unrelated peroxisome proliferators on mdr2 gene expression and biliary phospholipid output, and to explore the molecular mechanism(s) of mdr2 gene induction.

Methods: Male CFI mice were fed on a diet supplemented with several peroxisome proliferators: phenoxyacetic acid herbicides, plasticizers, acetylsalicylic acid and partially hydrogenated fish oil.

Results: Increased levels of mdr2 mRNAs, assessed by Northern blot analysis, were observed in the liver of mice treated with phenoxyacetic acid herbicides: 2,4,5-trichlorophenoxyacetic acid 570+/-133%, 2,4-dichlorophenoxyacetic acid 233+/-54% (p<0.005); plasticizers: di-(2-ethylhexyl)phthalate 282+/-78%, di-(isoheptyl)phthalate 163+/-40%, phthalic acid dinonyl ester 225+/-48% (p<0.01); and partially hydrogenated fish oil 372+/-138% (p<0.005). P-glycoprotein traffic ATPase content increased in the canalicular domain of hepatocyte of mice treated with the herbicide 2,4,5-trichlorophenoxyacetic acid and with partially hydrogenated fish oil (108% and 87%, respectively, p<0.05) as well as biliary phospholipid output (106% and 74%, respectively, p<0.05). In 2,4,5-trichlorophenoxyacetic acid-fed mice we found five-fold increase on mdr2 transcription rate, assessed by nuclear run-off assay.

Conclusions: Peroxisome proliferators induce mdr2 gene, its encoded P-gp in the canalicular domain of hepatocytes and increase biliary phospholipid output. The modulation of mdr2 gene might be part of the pleiotrophic response of peroxisome proliferation in mice liver and seems to be regulated mainly at a transcriptional level.