Altered Expressions of Hepatic Cyp2b1, Cyp3a, Ugt1a6 and Mdr1 in Non-Alcoholic Fatty Liver Disease in Rats

Abstract

Non-alcoholic fatty liver diseases include simple fatty liver (SFL) and non-alcoholic steatohepatitis (NASH). These liver disease states may affect the expression and function of various hepatic drug metabolizing enzymes and transporters (DMETs), potentially leading to altered pharmacokinetics, therapeutic efficacy and toxicity. This study focused on the investigation of changes in the expression of hepatic CYP2B1, CYP3A, UGT1A6, and MDR1 which have not yet been clarified sufficiently in rat models of SFL and/or NASH. Male Sprague-Dawley rats were randomly placed into one of three diet treatment groups: (1) normal diet (control) group for healthy liver, (2) high fat diet (HFD) group to induce SFL and (3) methionine-choline deficient diet (MCD) group to induce NASH. To confirm the induction of SFL and NASH, liver histology in these groups was evaluated by haematoxylin and eosion (H&E) staining. The mRNA and protein expression levels of DMETs studied were determined by real-time PCR and Western Blot analysis. Compared with control rats, significant increases in GOT, GPT level were observed in MCD groups. Several discernible histological differences in H&E staining were observed in HFD and MCD rats. The mRNA and protein expression levels of hepatic CYP3A and MDR1 in MCD rats were significantly higher than those in the other two groups. For CYP2B1, its mRNA expression levels in both HFD and MCD rats were significantly higher than those in control rats, while its protein expression levels were significantly higher only in MCD rats than those in the other two groups. For UGT1A6, its mRNA expression levels in both HFD and MCD rats were significantly higher than those in control rats, while its protein expression levels were significantly higher only in MCD rats than those in the other two groups. In conclusion, animal models of NAFLD including SFL and NASH were established. The NAFLD animal model showed altered expressions of Cyp2b1, Cyp3a, Ugt1a6 and Mdr1, which may indicate the possibility of altered expressions of enzymes in human NAFLD and of changing the pharmacokinetics of their substrate drugs.