OVEREXPRESSION OF MDR2 GENE BY PEROXISOME PROLIFERATORS IN THE MOUSE-LIVER

Background: In mice, fibrates induce mdr2 gene expression, and its enc oded P-glycoprotein in the canalicular domain of hepatocytes, as,yell as increasing biliary phospholipid output. It is not known whether thi s effect is restricted to fibrates or is a common property of peroxiso me proliferators. Aims: To test the effect of structurally unrelated p eroxisome proliferators on mdr2 gene expression and biliary phospholip id output, and to explore the molecular mechanism(s) of mdr2 gene indu ction. Methods: Male CFI mice were fed on a diet supplemented with sev eral peroxisome proliferators: phenoxyacetic acid herbicides, plastici zers, acetylsalicylic acid and partially hydrogenated fish oil. Result s: Increased levels of mdr2 mRNAs, assessed by Northern blot analysis, were observed in the liver of mice treated with phenoxyacetic acid he rbicides: 2,4,5-trichlorophenoxyacetic acid 570 +/- 133%, 2,4-dichloro phenoxyacetic acid 233 +/- 54% (p<0.005); plasticizers: di-(2-ethylhex yl)phthalate 282 +/- 78%, di-(isoheptyl)phthalate 163 +/- 40%, phthali c 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 wit h the herbicide 2,4,5-trichlorophenoxyacetic acid and with partially h ydrogenated fish oil (108% and 87%, respectively, p<0.05) as well as b iliary phospholipid output (106% and 74%, respectively, p<0.05). In 2, 4,5-trichlorophenoxyacetic acid-fed mice we found five-fold increase o n mdr2 transcription rate, assessed by nuclear run-off assay. Conclusi ons: Peroxisome proliferators induce mdr2 gene, its encoded P-gp in th e 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 reg ulated mainly at a transcriptional level.