Effect of bezafibrate on hepatic oxidative stress: comparison between conventional experimental doses and clinically-relevant doses in mice.
Several rodent studies have demonstrated that fibrate drugs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and increase reactive oxygen species (ROS) production. The persistence of strong PPARalpha 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 PPARalpha 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 PPARalpha-dependent manner, likely from discordant induction of PPARalpha-regulated ROS-generating enzymes (acyl-CoA oxidase, cytochrome P450 4A, and NADPH oxidase) and enhancement of mitochondrial beta-oxidation. The treatment also activated protein kinase C and phosphatidylinositol-3-kinase in wild-type mice only, suggesting an association between strong PPARalpha activation and an altered cell signaling cascade. Meanwhile, low-dose bezafibrate reduced serum/liver triglycerides in both genotypes without activating PPARalpha or enhancing hepatic oxidative stress. These results may support the safety of bezafibrate treatment at clinically-relevant doses.
Nakajima
Takero
T
Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Tanaka
Naoki
N
Li
Gang
G
Hu
Rui
R
Kamijo
Yuji
Y
Hara
Atsushi
A
Aoyama
Toshifumi
T
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001629:Bezafibrate / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D001629:Bezafibrate