Statins inhibit expression of thioredoxin reductase 1 in rat and human liver and reduce tumour development.
BACKGROUND
Statins have been reported to have anti-carcinogenic properties in addition to their cholesterol-lowering effects, but the mechanism is unknown. Thioredoxin reductases (TrxR) are selenium-containing enzymes of great importance for carcinogenesis and their levels are increased in neoplastic cells. The aim of the present study was to investigate if statin treatment is associated with alterations in the hepatic expression of TrxR.


METHODS
Human liver biopsies from a study where patients had been randomised to statin treatment or placebo were analysed. In addition we used liver tissue from a human liver bank where statin treated subjects were compared with non-treated. We also used tissue from a rat liver cancer model in which we have previously shown anti-carcinogenic effects of statins. Real-time PCR and activity assay were used to determine TrxR-levels and activity in tissue extracts.


RESULTS
In humans 80 mg atorvastatin treatment for 4 weeks (n = 6) was associated with 85% lower levels of TrxR1 and TrxR2 compared to placebo-treated patients (n = 8) (p = 0.03). In liver biopsies from a human donor liver bank 3 statin treated subjects had 90% lower expression of TrxR1 than 15 non-treated subjects (p = 0.04). Statin treatment was associated with 45% lower expression and activity of TrxR1 in a rat model for liver cancer (p = 0.03). There was a clear correlation between inhibition of carcinogenesis and decreased TrxR1-levels (p = 0.003).


CONCLUSIONS
Statin treatment decreases the hepatic expression of TrxR1 in humans and rats. Suppression of TrxR1 expression could explain possible anti-carcinogenic effects of statins. In addition, decreased levels of TrxR1 during statin treatment may shed light on the mechanism of other side-effects of statins.
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Cristine
C
Skogastierna
Maria
M
Johansson
Paolo
P
Parini
Mats
M
Eriksson
Lennart C
LC
Eriksson
Lena
L
Ekström
Linda
L
Björkhem-Bergman
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008113:Liver Neoplasms / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D054481:Thioredoxin Reductase 1