Diet-induced obese alters the expression and function of hepatic drug-metabolizing enzymes and transporters in rats

Abstract

Obesity increases the incidences of metabolic syndrome, including type 2 diabete, fatty liver, dyslipidemia, hyperglycemia, heart disease, hypertension and cancer. In particular, pharmacokinetics and pharmacodynamics of many drugs have changed in obese patients. However, little is known about the hepatic drug-metabolizing enzymes and transporters that are influenced by diet-induced obese. In this report, we established obesity and fatty liver models in male rats by high-fat diet. The expression profiles of drug-metabolizing enzymes and transporters were studied by quantitative real-timePCR and Western blotting analysis. The function of these enzymes and transporters were assessed by their substrates and cocktail methods. The expression and activity of phase I enzymes (CYP1A2, CYP2B1, CYP2C11, CYP3A1, CYP4A1 and FMO1) and phase II enzymes (UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, NAT1 and GSTT1) were decreased in the liver of obese rats. In addition, the mRNA levels of hepatic transporter Slco1a2, Slco1b2, Slc22a5, Abcc2, Abcc3, Abcb1a and Abcg2 decreased significantly in obese animals, while Abcb1b increased significantly. Furthermore, the decreased expression of hepatic phase I and II enzymes and transporter may be due to changes of Hnf4α, LXRα and FXR. In conclusion, the diet-induced obese altered the expression and function of hepatic drug-metabolizing enzymes and transporters in male rats, thereby impacting drug metabolism and pharmacokinetics.