Flutamide Induces Hepatic Cell Death and Mitochondrial Dysfunction via Inhibition of Nrf2-Mediated Heme Oxygenase-1

Abstract

Flutamide is a widely used nonsteroidal antiandrogen for prostate cancer therapy, but its clinical application is restricted by the concurrent liver injury. Increasing evidence suggests that flutamide-induced liver injury is associated with oxidative stress, though the precise mechanism is poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidants including heme oxygenase-1 (HO-1). This study was designed to delineate the role of Nrf2/HO-1 in flutamide-induced hepatic cell injury. Our results showed that flutamide concentration dependently induced cytotoxicity, hydrogen peroxide accumulation, and mitochondrial dysfunction as indicated by mitochondrial membrane potential loss and ATP depletion. The protein expression of Nrf2 and HO-1 was induced by flutamide at 12.5 μM but was downregulated by higher concentrations of flutamide. Silencing either Nrf2 or HO-1 was found to aggravate flutamide-induced hydrogen peroxide accumulation and mitochondrial dysfunction as well as inhibition of the Nrf2 pathway. Moreover, preinduction of HO-1 by Copp significantly attenuated flutamide-induced oxidative stress and mitochondrial dysfunction, while inhibition of HO-1 by Snpp aggravated these deleterious effects. These findings suggest that flutamide-induced hepatic cell death and mitochondrial dysfunction is assoicated with inhibition of Nrf2-mediated HO-1. Pharmacologic intervention of Nrf2/HO-1 may provide a promising therapeutic approach in flutamide-induced liver injury.

Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway

“…Previous research in our laboratory showed that flutamide-induced hepatic cell death, oxidative stress and mitochondrial dysfunction were mediated by Nrf2 pathway inhibition (Zhang, Guo, et al, 2018).…”

“…On the contrary, the inhibition of the Nrf2 pathway is implicated in drug‐induced organ damage (Zhang, Wang, Velkov, Tang, & Dai, ). Previous research in our laboratory showed that flutamide‐induced hepatic cell death, oxidative stress and mitochondrial dysfunction were mediated by Nrf2 pathway inhibition (Zhang, Guo, et al, ). In the present study, expression levels of Nrf2 and SOD2 in HepG2 cells were decreased under high‐dose ATO, while the Nrf2 activator TBHQ restored Nrf2 and SOD2 expression and mitigated mitochondrial damage and apoptosis, suggesting that sufficient Nrf2 pathway activity is essential for protection against ATO‐induced hepatotoxicity and that upregulation of Nrf2 is a feasible protective strategy to prevent ATO hepatotoxicity.…”

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

“…ROS increases cell apoptosis in testosterone-deprived men and male rats (94), which were attenuated by exogenous testosterone supplementation (95). Inhibition of AR activity by flutamide also increased ROS (H 2 O 2 ) levels and damaged mitochondria, as indicated by a drop in the mitochondrial membrane potential and ATP production in cultured hepatocytes (46). Therefore, these results suggest that androgen/AR may reduce ROS and protect the mitochondrial respiratory chain.…”

“…Other mitochondrial proteins, such as NIX, BNIP3, and FUNDC1, are also involved in mitophagy, and a defect in any of those molecules may contribute to impaired mitophagy. A defect in mitophagy has been reported in the pathogenesis of insulin resistance in several studies (44)(45)(46). Therefore, dysregulation of the mitochondria quality control process may lead to mitochondrial dysfunction in the pathogenesis of insulin resistance.…”

“…Androgens are responsible for maintaining the structural integrity of the mitochondrial respiratory chain. A study in vitro showed that the AR antagonist, flutamide, decreased complex I activity, mitochondrial membrane potential, and ATP production (by almost 51.2%) in cultured hepatocytes (46,85). This fall in mitochondrial membrane potential leads to an upregulation of permeability transition pore (PTP) openings, resulting in loss of mitochondrial content and cristae (86).…”