Silymarin is known for its hepatoprotective activity whereas propolis and OPC are strong antioxidants with vascular dilating effects. This study provides a possible molecular mechanism for the beneficial effects attributed to these natural drugs including the upregulation of detoxifying UGT1A enzymes by activation of XRE and ARE binding elements in the respective promoters. selleck inhibitor However, the intake of these

drugs could influence the clearance of other drugs and therefore result in adverse effects when combined with other medications undergoing glucuronidation. Furthermore, the UGT1A mediated antioxidant effects of silymarin, propolis and OPC are affected by frequently occurring genetic variants of UGT1A promoters. Small molecule library molecular weight Disclosures: Michael P. Manns – Consulting: Roche, BMS,

Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis The following people have nothing to disclose: Sandra Kalthoff, Anja Winkler, Christian P. Strassburg Purpose: Occupational vinyl chloride (VC) exposures have been linked to toxicant associated steatohepatitis (TASH), although the modes of action are largely unknown. Circulating levels of oxidized metabolites of linoleic acid (OXLAMs) were elevated in previous studies of alcoholic (ASH) and nonalcoholic steatohepatitis (NASH), although the potential pathologic role of OXLAMS in steatohepatitis is unknown. The aim of the present study was to determine whether VC exposure is associated with increased plasma OXLAMs, and learn more to evaluate potential mechanisms of OXLAM hepatotoxicity. Methods: Human Study:

Archived serum samples from highly exposed male VC workers with high-level VC exposures (n=17) and unexposed healthy volunteers (n=27) were obtained from the UofL Occupational Toxicology Specimen Bank. Plasma metabolomic analyses were performed by GC/MS (Thermo-Finnigan Trace DSQ fast-scanning single-quadrupole mass spectrometer) and LC/MS/MS (Waters ACQUITY UPLC, Thermo-Finnigan LTQ mass spectrometer) following metabolite extraction. In-vitro Experiments: HepG2 cells were exposed to linoleic acid and multiple OXLAM isoforms overnight. Seahorse and Cellomics analysis were performed to evaluate effects of treatments on mitochondria function, ER stress, and cell survival. Results: 613 unique named metabolites were identified in plasma of the VC workers. Of these, 189 metabolites were significantly increased in the VC exposure group while 94 metabolites were significantly decreased. Essential (7 of 7) and long chain free fatty acids (19 of 19) were significantly increased with VC exposure.