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. 2013 Jul 19;15(3):123–130. doi: 10.1179/174329210X12650506623807

Effect of bezafibrate on hepatic oxidative stress: comparison between conventional experimental doses and clinically-relevant doses in mice

Takero Nakajima 1, Naoki Tanaka 2, Gang Li 3, Rui Hu 4, Yuji Kamijo 1, Atsushi Hara 1, Toshifumi Aoyama 1
PMCID: PMC7067332  PMID: 20594415

Abstract

Several rodent studies have demonstrated that fibrate drugs can activate peroxisome proliferator-activated receptor α (PPARα) and increase reactive oxygen species (ROS) production. The persistence of strong PPARα activation is considered to be a possible mechanism related to the adverse effects of these agents in humans. We recently found that bezafibrate-treated mice at clinically-relevant doses (10 mg/kg/day) exhibited similar pharmacokinetics to humans, but were different from previous rodent data (> 50 mg/kg/day). To examine whether clinical doses of bezafibrate do in fact activate PPARα and increase hepatic oxidative stress in mice, we administered bezafibrate to wild-type and Ppara-null mice at high (100 mg/kg/day) or low (10 mg/kg/day) doses and assessed ROS-related pathways in the liver. High-dose bezafibrate increased hepatic lipid peroxides in a PPARα-dependent manner, likely from discordant induction of PPARα-regulated ROS-generating enzymes (acyl-CoA oxidase, cytochrome P450 4A, and NADPH oxidase) and enhancement of mitochondrial β-oxidation. The treatment also activated protein kinase C and phosphatidylinositol-3-kinase in wild-type mice only, suggesting an association between strong PPARα activation and an altered cell signaling cascade. Meanwhile, low-dose bezafibrate reduced serum/liver triglycerides in both genotypes without activating PPARα or enhancing hepatic oxidative stress. These results may support the safety of bezafibrate treatment at clinically-relevant doses.

Keywords: BEZAFIBRATE, OXIDATIVE STRESS, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α (PPARα)

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