β‐Naphthoflavone‐Induced Mitochondrial Respiratory Damage in Cyp1 Knockout Mouse and in Cell Culture Systems: Attenuation by Resveratrol Treatment

Abstract

A number of xenobiotic-inducible cytochrome P450s (CYPs) are now known to be localized in the mitochondrial compartment, though their pharmacological or toxicological roles remain unclear. Here, we show that BNF treatment markedly inhibits liver mitochondrial O2 consumption rate (OCR), ADP-dependent OCR, and also reserve OCR, in wild-type mice but not in Cyp1a1/1a2(−/−) double knockout mice. BNF treatment markedly affected mitochondrial complex I and complex IV activities and also attenuated mitochondrial gene expression. Furthermore, under in vitro conditions, BNF treatment induced cellular ROS production, which was inhibited by mitochondria-targeted antioxidant Mito-CP and CYP inhibitor proadefin, suggesting that most of the ROS production was intramitochondrial and probably involved the catalytic activity of mitochondrial CYP1 enzymes. Interestingly, our results also show that the AHR antagonist resveratrol, markedly attenuated BNF-induced liver mitochondrial defects in wild-type mice, confirming the role of AHR and AHR-regulated CYP1 genes in eliciting mitochondrial dysfunction. These results are consistent with reduced BNF-induced mitochondrial toxicity in Cyp1a1/1a2(−/−) mice and elevated ROS production in COS cells stably expressing CYP1A1. We propose that increased mitochondrial ROS production and respiratory dysfunction are part of xenobiotic toxicity. Resveratrol, a chemopreventive agent, renders protection against BNF-induced toxicity.

Baicalein Inhibits Benzo[a]pyrene-Induced Toxic Response by Downregulating Src Phosphorylation and by Upregulating NRF2-HMOX1 System

“…Since BaP is lipophilic, it easily crosses the cell membrane, binds to its receptor AHR, and triggers the AHR nuclear translocation, and subsequently upregulates xenobiotic metabolizing enzymes such as CYP1A1 which metabolizes BaP [6,[8][9][10][17][18][19][20][21][22][23]. Resulting metabolites undergo redox cycles with generation of ROS and leading to oxidative stress [6,24,25]. The generated oxidative stress further stimulates the production of proinflammatory cytokines [7,[26][27][28][29][30][31].…”

“…The generated oxidative stress further stimulates the production of proinflammatory cytokines [7,[26][27][28][29][30][31]. The flow of these reactions and emersion of hazardous effects by BaP or by other PAHs appear to be highly dependent on the AHR-CYP1A1 axis because they are attenuated in Ahr-deficient mice [64][65][66] and in Cyp1a1-deficient mice [24,25].…”

“…When it binds to AHR, BaP is oxidized by CYPs into epoxides and phenolic intermediates, which are further processed by phase II enzymes. The resulting 3,6-quinone undergoes redox cycles with generation of reactive oxygen species (ROS) and leads to oxidative stress [6,24,25]. The oxidative stress increases secretion of ATP, which in turn stimulates the production of proinflammatory cytokines such as IL-1α, IL-1β, and IL-6 [7,[26][27][28][29][30][31].…”

Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne

“…As dioxin is very stable and persistent, the metabolizing process by CYP1A1 generates high levels of ROS ( Figure 1 ). In CYP1A1-deficient conditions, ROS production is profoundly attenuated [ 4 , 32 ]. ROS-mediated oxidative stress induces DNA damage and upregulates the production of inflammatory cytokines and chemokines, such as IL-8 and CCL2 from keratinocytes [ 1 , 4 , 33 ].…”

Potential Role of NRF2 Agonist in Managing AHR-Mediated Chloracne by Dioxin

“…1). In CYP1A1-deficient conditions, the ROS production is profoundly attenuated [4,32]. The ROS-mediated oxidative stress induces DNA damage and upregulates the production of inflammatory cytokines and chemokines such as IL-8 and CCL2 from keratinocytes [1,4,33].…”