Arsenic decreases RXRα-dependent transcription of CYP3A and suppresses immune regulators in hepatocytes.
Arsenite is critical pharmacologically as a treatment for advanced stage blood cancer. However, environmental exposure to arsenic results in multiple diseases. Previous studies have shown that arsenic decreases expression of CYP3A, a critical drug metabolizing enzyme in human and rat liver. In addition, acute and chronic arsenic exposure in liver stimulates an inflammatory response. Our work has shown that arsenite decreases nuclear levels of RXRα the nuclear receptor that, as a heterodimer partner with PXR, transactivates the CYP3A gene. These results suggest that arsenite decreases transcription of CYP3A by decreasing RXRα. The present report shows that exposure to 5 μM arsenite decreased the activity of a rat CYP3A promoter luciferase reporter in HepG2 cells. The activity of a RARE-luciferase reporter, that is transactivated by the retinoic acid receptor (RAR)/RXRα, was also decreased. Previous studies have shown that arsenic in the concentration range of 2-5 μM affects CYP3A mRNA. When rifampicin-treated primary human hepatocyte cultures were exposed to arsenite concentrations as low as 50 nM, CYP3A mRNA was decreased. Treatment of primary human hepatocytes with the proteasome inhibitor MG132 increased RXRα suggesting the involvement of the proteasome pathway in regulation of RXRα. Finally, arsenic induces a pro-inflammatory response in liver. Surprisingly, we show that in hepatocytes arsenite decreases expression of two inflammatory mediators, TNF and VEGF, an effect that is not predicted from suppression of RXRα activity.
Veterans Administration Medical Center, White River Junction, VT 05009, USA.
Trisha L
TL
Noreault-Conti
Abigail
A
Fellows
Judith M
JM
Jacobs
Heidi W
HW
Trask
Stephen C
SC
Strom
Ronald M
RM
Evans
Steven A
SA
Wrighton
Peter R
PR
Sinclair
Jacqueline F
JF
Sinclair
Ralph C
RC
Nichols
D000328:Adult; D018053:Arsenites / Q000633:toxicity*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D018053:Arsenites; D004785:Environmental Pollutants; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C015001:arsenite