The administration of a high-fat diet alters bile acid composition and hepatic drug metabolism in rats

Introduction: Nutrition might have a significant impact on the expression of genes involved in drug metabolism. In turn, bile acids can also regulate drug-metabolizing enzymes since they can activate the nuclear receptors responsible for their transcription. However, more insights are needed to understand the complex interplay between nutritional status, bile acid composition and the pharmacokinetics of drugs. Aims: To evaluate whether the administration of a high-fat diet (HFD) affects liver function, bile acid composition, and the hepatic expression of the two main drug-metabolizing enzymes CYP3A1 and CYP3A2, orthologues of the human CYP3A4, which is responsible for the metabolism of more than 50% of currently used drugs. Methods: HFD (60% fat) was administered to Wistar-Kyoto rats (n = 6) for 12 weeks; 6 rats fed with standard diet were used as controls. After sacrifice liver histology was performed and the main plasma biochemical parameters were measured. Plasma concentration of 6 bile acids (BAs) was determined by means of HUPLC-MS/MS. Hepatic gene and protein expressions of the two drug-metabolizing enzymes CYP3A1 and CYP3A2 were assessed by means of qRT-PCR and Western blot. Results were compared by Student’ t test, and p < 0.05 was considered statistically significant. Results: Liver histology of HFD rats didn’t show alterations with respect to controls. HFD induced a significant increase inAST and bilirubin levels (p < 0.01), and in the LDL/HDL index (p < 0.001). The concentration of the BAs CDCA and GCA increased significantly in HFD rats (p < 0.05), whereas CA significantly decreased (p < 0.05), as well as CYP3A1 and CYP3A2 gene (p < 0.01 for both isoforms) and protein (p < 0.05) expression. Conclusions: The administration of HFD for 12 weeks, although not causing hepatic histological alterations, alters liver function and BAs composition, and reduces significantly hepatic drug metabolism. Therefore, this diet should be considered a possible relevant source of metabolic drug interactions.