title: Simvastatin inhibits the core promoter of the TXNRD1 gene and lowers cellular TrxR activity in HepG2 cells.
abstract: Thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing redox-active enzyme that is thought to be important during carcinogenesis. We have recently shown that treatment with statins, HMGCoA reductase inhibitors, reduces the levels of TrxR1 in liver of both rat and human. The reduced TrxR1 levels were correlated with inhibited hepatocarcinogenesis in a rat model. The aim of the present study was to investigate if statins affect the activity of the human TXNRD1 core promoter, which guides expression of TrxR1, and if the effects by statins on TrxR1 expression in liver could be reproduced in a cellular model system. We found that simvastatin and fluvastatin decreased cellular TrxR activity in cultured human liver-derived HepG2 cells with approximately 40% (p<0.05). Simvastatin, but not fluvastatin or atorvastatin, also reduced the TXNRD1 promoter activity in HepG2 cells by 20% (p<0.01). In line with this result, TrxR1 mRNA levels decreased with about 25% in non-transfected HepG2 cells upon treatment with simvastatin (p<0.01). Concomitant treatment with mevalonate could not reverse these effects of simvastatin, indicating that other mechanisms than HMGCoA reductase inhibition was involved. Also, simvastatin did not inhibit sulforaphane-derived stimulation of the TXNRD1 core promoter activity, suggesting that the inhibition by simvastatin was specific for basal and not Nrf2-activated TrxR1 expression. In contrast to simvastatin, the two other statins tested, atorvastatin or fluvastatin, did not influence the TrxR1 mRNA levels. Thus, our results reveal a simvastatin-specific reduction of cellular TrxR1 levels that at least in part involves direct inhibitory effects on the basal activity of the core promoter guiding TrxR1 expression.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. lena.ekstrom@ki.se
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
authors.forename: Maria
authors.initials: M
authors.lastname: Johansson
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
authors.forename: Anna-Klara
authors.initials: AK
authors.lastname: Rundlöf
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
mesh_terms: D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D012333:RNA, Messenger; D000077340:Fluvastatin; D019821:Simvastatin; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1