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Status |
Public on Jul 31, 2017 |
Title |
Expression data of liver tissues from rats with and without methapyrilene treatment |
Organism |
Rattus norvegicus |
Experiment type |
Expression profiling by array
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Summary |
We investigated a drug-induced liver injury (DILI) model in rats induced by methapyrilene (MPy) administration. MPy, a former antihistamine and anticholinergic drug, was withdrawn in the 1970ties due to its ability to initiate hepatocarcinogenesis and is now used to induce hepatobiliary injury and biliary epithelial cell hyperplasia. Male Wistar rats (8–10 weeks old, weighing 170–200 g) were randomly assigned to three dosing groups (n=6 per group and time-point) and dosed with MPy at 0, 30 and 80 mg/kg/day by oral gavage. After 4, 8 or 15 days, or after 14 days followed by a recovery period of 10 days (day 24) rats were sacrificed. Increased levels of ALAT, ASAT, AP and ɣ-GT as well as bili-t and total bile acids indicated liver damage (AP and ɣGT indicating biliary effects). They were detectable on day 7 at the high dose of 80 mg/kg MPy and persisted until day 15 at end of treatment. Histopathologically, vacuolation and necrosis of the hepatocytes (predominantly in the periportal region) were seen starting on day 3 - especially in animals treated with 80 mg/kg MPy. These findings were accompanied by periportal mononuclear inflammatory cell filtration. Bile duct proliferation, bile duct hyperplasia and increased numbers of mitoses of hepatocytes were evident at all treatment time points. The frequency and severity of these findings increased with dose and duration of the treatment. Gene expression analysis in liver tissues revealed highly significant transcriptional changes in the high dose group, detectable on day 4 and intensifying over time. Besides genes associated with apoptosis (CASP4, CASP12), detoxification (CYB4B) and proliferation (p21, CCNG1) several were related to bile acid metabolism or transport. For example, bile acid exporters OATP1, NTCP, OATP4 and MOAT1/ OATPB as well as the putative bile acid metabolizing enzymes AMACR, BAAT and ACOX2 were found down regulated in response to MPy treatment. In contrast, mRNAs encoding putative bile acid importers MRP2 and ABCC4 / MRP4 were found up regulated. Most of the deregulated levels returned to control values during the recovery phase except OATP1, MOAT1/ OATPB, which remained slightly elevated. Interestingly, OATP4 followed an inverse trend of deregulation after 10 days of recovery, presumably due to overcompensation. Overall, the expression changes found associated with bile acid metabolism or transport could be linked to detected bile acid level alterations in liver and plasma.
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Overall design |
Male Wistar rats were (8–10 weeks old, weighing 170–200 g) were randomly assigned to three dosing groups (n=6 per group and time-point) and dosed with methapyrilene (Sigma-Aldrich; in carboxymethylcellulose) at 0, 30 and 80 mg/kg/day by oral gavage. Rats were sacrificed after 4, 8 or 15 days, or after 14 days of treatment followed by a recovery period of 10 days (assigned as day 24).
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Contributor(s) |
Pavkovic M, Riefke B, Ellinger-Ziegelbauer H, Slopianka M |
Citation(s) |
28529062 |
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Submission date |
Feb 28, 2017 |
Last update date |
Oct 30, 2017 |
Contact name |
Heidrun Christine Ellinger-Ziegelbauer |
E-mail(s) |
heidrun.ellinger-ziegelbauer@bayer.com
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Organization name |
Bayer Pharma AG
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Street address |
Aprather Weg 18a
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City |
Wuppertal |
ZIP/Postal code |
42096 |
Country |
Germany |
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Platforms (1) |
GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
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Samples (57)
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GSM2514657 |
Control liver day 4, biological rep4 |
GSM2514658 |
Control liver day 4, biological rep5 |
GSM2514659 |
Control liver day 8, biological rep1 |
GSM2514660 |
Control liver day 8, biological rep2 |
GSM2514661 |
Control liver day 8, biological rep3 |
GSM2514662 |
Control liver day 8, biological rep4 |
GSM2514663 |
Control liver day 8, biological rep5 |
GSM2514664 |
Control liver day 15, biological rep1 |
GSM2514665 |
Control liver day 15, biological rep2 |
GSM2514666 |
Control liver day 15, biological rep3 |
GSM2514667 |
Control liver day 15, biological rep4 |
GSM2514668 |
Control liver day 15, biological rep5 |
GSM2514669 |
Control liver day 24, biological rep2 |
GSM2514670 |
Control liver day 24, biological rep3 |
GSM2514671 |
Control liver day 24, biological rep4 |
GSM2514672 |
Control liver day 24, biological rep5 |
GSM2514673 |
30mg/kg MPy liver day 4, biological rep1 |
GSM2514674 |
30mg/kg MPy liver day 4, biological rep2 |
GSM2514675 |
30mg/kg MPy liver day 4, biological rep3 |
GSM2514676 |
30mg/kg MPy liver day 4, biological rep4 |
GSM2514677 |
30mg/kg MPy liver day 4, biological rep5 |
GSM2514678 |
30mg/kg MPy liver day 8, biological rep1 |
GSM2514679 |
30mg/kg MPy liver day 8, biological rep2 |
GSM2514680 |
30mg/kg MPy liver day 8, biological rep3 |
GSM2514681 |
30mg/kg MPy liver day 8, biological rep4 |
GSM2514682 |
30mg/kg MPy liver day 8, biological rep5 |
GSM2514683 |
30mg/kg MPy liver day 15, biological rep1 |
GSM2514684 |
30mg/kg MPy liver day 15, biological rep2 |
GSM2514685 |
30mg/kg MPy liver day 15, biological rep3 |
GSM2514686 |
30mg/kg MPy liver day 15, biological rep4 |
GSM2514687 |
30mg/kg MPy liver day 15, biological rep5 |
GSM2514688 |
30mg/kg MPy liver day 24, biological rep1 |
GSM2514689 |
30mg/kg MPy liver day 24, biological rep2 |
GSM2514690 |
30mg/kg MPy liver day 24, biological rep3 |
GSM2514691 |
30mg/kg MPy liver day 24, biological rep4 |
GSM2514692 |
80mg/kg MPy liver day 4, biological rep2 |
GSM2514693 |
80mg/kg MPy liver day 4, biological rep3 |
GSM2514694 |
80mg/kg MPy liver day 4, biological rep4 |
GSM2514695 |
80mg/kg MPy liver day 4, biological rep5 |
GSM2514696 |
80mg/kg MPy liver day 8, biological rep1 |
GSM2514697 |
80mg/kg MPy liver day 8, biological rep2 |
GSM2514698 |
80mg/kg MPy liver day 8, biological rep3 |
GSM2514699 |
80mg/kg MPy liver day 8, biological rep4 |
GSM2514700 |
80mg/kg MPy liver day 8, biological rep5 |
GSM2514701 |
80mg/kg MPy liver day 15, biological rep1 |
GSM2514702 |
80mg/kg MPy liver day 15, biological rep2 |
GSM2514703 |
80mg/kg MPy liver day 15, biological rep3 |
GSM2514704 |
80mg/kg MPy liver day 15, biological rep4 |
GSM2514705 |
80mg/kg MPy liver day 15, biological rep5 |
GSM2514706 |
80mg/kg MPy liver day 24, biological rep1 |
GSM2514707 |
80mg/kg MPy liver day 24, biological rep2 |
GSM2514708 |
80mg/kg MPy liver day 24, biological rep3 |
GSM2514709 |
80mg/kg MPy liver day 24, biological rep4 |
GSM2514710 |
80mg/kg MPy liver day 24, biological rep5 |
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Relations |
BioProject |
PRJNA377224 |
Supplementary file |
Size |
Download |
File type/resource |
GSE95470_RAW.tar |
138.4 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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