TY - JOUR
T1 - Hypercholesterolemia reduces the expression and function of hepatic drug metabolizing enzymes and transporters in rats
AU - Xu, Yuan
AU - Lu, Jian
AU - Guo, Yuanqing
AU - Zhang, Yuanjin
AU - Liu, Jie
AU - Huang, Shengbo
AU - Zhang, Yanfang
AU - Gao, Liangcai
AU - Wang, Xin
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
KW - Drug-metabolizing enzyme
KW - Hypercholesterolemia
KW - Nuclear receptor
KW - Pharmacokinetics
KW - Transporter
UR - https://www.scopus.com/pages/publications/85131426559
U2 - 10.1016/j.toxlet.2022.05.009
DO - 10.1016/j.toxlet.2022.05.009
M3 - 文章
C2 - 35654319
AN - SCOPUS:85131426559
SN - 0378-4274
VL - 364
SP - 1
EP - 11
JO - Toxicology Letters
JF - Toxicology Letters
ER -