Hypercholesterolemia reduces the expression and function of hepatic drug metabolizing enzymes and transporters in rats. (1st July 2022)

• Record Type: Journal Article
• Authors: Xu, Yuan; Lu, Jian; Guo, Yuanqing; Zhang, Yuanjin; Liu, Jie; Huang, Shengbo; Zhang, Yanfang; Gao, Liangcai; Wang, Xin
• Is Part Of: Toxicology letters. Volume 364(2022)
• Page Start: 1
• Page End: 11
• Publication Date: 2022-07-01
• Subjects: ABC ATP-binding cassette -- ADME absorption, distribution, metabolism and excretion -- ASCT2 alanine-serine-cysteine transporter 2 -- BCRP breast cancer resistance protein -- CVD cardiovascular disease -- CYP cytochrome P450 -- DMPK drug metabolism and pharmacokinetics -- FMOs flavin-containing monooxygenases -- GST glutathione-S-transferase -- HCD high cholesterol diet -- HDL-C high-density lipoproteins-cholesterol -- HE hematoxylin & eosin -- ND normal diet -- LDL-C low-density lipoproteins-cholesterol -- LDL low density lipoprotein -- MDR1 multidrug resistance protein 1 -- MRP2 multidrug resistance-associated protein 2 -- NAFLD non-alcoholic fatty liver disease -- NASH non-alcoholic steatohepatitis -- NAT N-acetyltransferase -- NC nitrocellulose -- OATP organic anion-transporting polypeptide -- SD Sprague-Dawley -- SLC solute carrier -- SMCT1 sodium-coupled monocarboxylate transporter 1 -- SULT sulfotransferase -- TCH total cholesterol -- TRIG triglycerides -- UGT UDP glucuronosyltransferase; Hypercholesterolemia -- Pharmacokinetics -- Drug-metabolizing enzyme -- Transporter -- Nuclear receptor; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.05.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Hypercholesterolemia, one of the most common lipid metabolic diseases, may cause severe complications and even death. However, the effect of hypercholesterolemia on drug-metabolizing enzymes and transporters remains unclear. In this report, we established a rat model of diet-induced hypercholesterolemia. Quantitative real-time PCR and Western blot analysis were used to study the mRNA and protein expression of drug-metabolizing enzymes and transporters. The functions of these enzymes and transporters were evaluated by the cocktail assay. In hypercholesterolemic rats, the expression of phase I enzymes (CYP1A2, CYP2C11, CYP2E1, CYP3A1/2, CYP4A1 and FMO1/3) and phase II enzymes (UGT1A1/3, PROG, AZTG, SULT1A1, NAT1 and GSTT1) decreased. In addition, the mRNA levels of drug transporter Slco1a1/2, Slco1b2, Slc22a5, Abcc2, Abcb1a and Abcg2 decreased in rats with hypercholesterolemia, while Abcb1b and Abcc3 increased. The decreased expression of hepatic phase I and II enzymes and transporters may be caused by the changes of CAR, FXR, PXR, and Hnf4α levels. In conclusion, diet-induced hypercholesterolemia changes the expression and function of hepatic drug-metabolizing enzymes and transporters in rats, thereby possibly affecting drug metabolism and pharmacokinetics. In clinical hyperlipidemia, patients should strengthen drug monitoring to avoid possible drug exposure mediated risks. Graphical Abstract: ga1 Highlights: The expression and activity of drug metabolizing enzymes (DME) decreased significantly in hypercholesterolemic rats. The mRNA expression of drug transporters changed in hypercholesterolemic rats. The decreased expression of DME and transporters may be caused by the changes of CAR, FXR, PXR, and Hnf4α . Hypercholesterolemia changes the expression and function of DME and transporters in rats.