title: Peroxisome Proliferator-Activated Receptor α Activation Suppresses Cytochrome P450 Induction Potential in Mice Treated with Gemfibrozil.
abstract: Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates.
authors.affiliation: First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Cunzhong
authors.initials: C
authors.lastname: Shi
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Min
authors.affiliation: Ningbo College of Health Sciences, Ningbo, China.
authors.forename: Julin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Manyun
authors.initials: M
authors.lastname: Dai
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Danjun
authors.initials: D
authors.lastname: Song
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Hua
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Gangming
authors.initials: G
authors.lastname: Xu
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Medical School of Ningbo University, Ningbo, China.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
mesh_terms: D000818:Animals; D019362:Cytochrome P-450 CYP2B1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D065687:Cytochrome P-450 CYP2C8 Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D015248:Gemfibrozil