In:
Biochemical Journal, Portland Press Ltd., Vol. 350, No. 2 ( 2000-09-01), p. 443-451
Abstract:
P-Glycoprotein transporters encoded by mdr1 (multidrug resistance) genes mediate extrusion of an array of lipophilic xenobiotics from the cell. In rat liver, mdr transcripts have been shown to be expressed mainly in hepatocytes of the periportal region. Since gradients in oxygen tension (pO2) may contribute towards zonated gene expression, the influence of arterial and venous pO2 on mRNA expression of the mdr1b isoform was examined in primary rat hepatocytes cultured for up to 3 days. Maximal mdr1b mRNA levels (100%) were observed under arterial pO2 after 72h, whereas less than half-maximal mRNA levels (40%) were attained under venous pO2. Accordingly, expression of mdr protein and extrusion of the mdr1 substrate rhodamine 123 were maximal under arterial pO2 and reduced under venous pO2. Oxygen-dependent modulation of mdr1b mRNA expression was prevented by actinomycin D, indicating transcriptional regulation. Inhibition of haem synthesis by 25µM CoCl2 blocked mdr1b mRNA expression under both oxygen tensions, whereas 80µM desferrioxamine abolished modulation by O2. Haem (10µM) increased mdr1b mRNA levels under arterial and venous pO2. In hepatocytes treated with 50µM H2O2, mdr1b mRNA expression was elevated by about 1.6-fold at venous pO2 and 1.5-fold at arterial pO2. These results support the conclusion that haem proteins are crucial for modulation of mdr1b mRNA expression by O2 in hepatocyte cultures and that reactive oxygen species may participate in O2-dependent signal transduction. Furthermore, the present study suggests that oxygen might be a critical modulator for zonated secretion of mdr1 substrates into the bile.
Type of Medium:
Online Resource
ISSN:
0264-6021
,
1470-8728
Language:
English
Publisher:
Portland Press Ltd.
Publication Date:
2000
detail.hit.zdb_id:
1473095-9
SSG:
12
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