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Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors clinically used for hyperlipidemia.Statins are generally safe but can induce cholestasis.The present study aimed to examine the effects of atorvastatin at high doses on hepatic gene expression related to bile acid metabolism and homeostasis,as well as the expression of circadian clock genes in mice.Adult male mice were given atorvastatin (10,30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology,and gene expression were examined.Repeated administration of atorvastatin did not affect animal body weight gain or liver weights.Serum enzyme activities were in the normal range.Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration,inflammatory cell infiltration, together with increased expression of Egr-1 and metallothionein-1.Atorvastatin increased the expression of Cyp7a1 in the liver,along with FXR and SHP.In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ.The most dramatic change was the 30-fold induction of Cyp7a1.Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression.Atorvastatin increased Bmal1 and Npas2 similar to Cyp7a1, but decreased the expression of Per2, Per3, Dbp and Tef,whereas it had no effect on Cry1 and Rev-erbα expression.Thus,repeated administration of atorvastatin at high doses affects bile acid metabolism and disposition and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1 ,together with alterations in the expression of circadian clock genes.