The aflatoxin B₁‐fumonisin B₁ toxicity in BRL‐3A hepatocytes is associated to induction of cytochrome P450 activity and arachidonic acid metabolism

Abstract

Human oral exposure to aflatoxin B (AFB ) and fumonisin B (FB ) is associated with increased hepatocellular carcinoma. Although evidence suggested interactive AFB -FB hepatotoxicity, the underlying mechanisms remain mostly unidentified. This work was aimed at evaluating the possible AFB -FB interplay to induce genetic and cell cycle toxicities in BRL-3A rat hepatocytes, reactive oxygen species (ROS) involvement, and the AFB metabolizing pathways cytochrome P450 (CYP) and arachidonic acid (ArAc) metabolism as ROS contributors. Flow cytometry of stained BRL-3A hepatocytes was used to study the cell cycle (propidium iodide), ROS intracellular production (DCFH-DA, HE, DAF-2 DA), and phospholipase A activity (staining with bis-BODIPY FL C11-PC). The CYP1A activity was assessed by the 7-ethoxyresorufin-O-deethylase (EROD) assay. Despite a 48-h exposure to FB (30 μM) not being genotoxic, the AFB (20 μM)-induced micronucleus frequency was overcome by the AFB -FB mixture (MIX), presumably showing toxin interaction. The mycotoxins blocked G1/S-phase, but only MIX caused cell death. Overall, the oxidative stress led these alterations as the pretreatment with N-acetyl-l-cysteine reduced such toxic effects. While AFB had a major input to the MIX pro-oxidant activity, with CYP and ArAc metabolism being ROS contributors, these pathways were not involved in the FB -elicited weak oxidative stress. The MIX-induced micronucleus frequency in N-acetyl-l-cysteine pretreated cells was greater than that caused by AFB without antioxidants, suggesting enhanced AFB direct genotoxicity probably owing to the higher CYP activity and ArAc metabolism found in MIX. The metabolic pathways modulation by AFB -FB mixtures could raise its hepatocarcinogenic properties.

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

“…TiO 2 NPs stimulated the expression of CYP enzymes, such as Cyp4a14 and Cyp2b9. CYP enzymes expressed throughout the human body play a crucial role in human physiology and are involved in drug and xenobiotic metabolism as well as biosynthesis of endogenous molecules . During the CYP catalytic cycle, ROS is generated through uncoupling of the enzymatic cycle .…”

“…19,20 In our experiments, Res relieved ER stress and ROS generation and CYP enzymes expressed throughout the human body play a crucial role in human physiology and are involved in drug and xenobiotic metabolism as well as biosynthesis of endogenous molecules. 21,22 During the CYP catalytic cycle, ROS is generated through uncoupling of the enzymatic cycle. 23 Two pathways exist within the CYP catalytic cycle, which can generate ROS without completion of substrate oxidation, a process known as "reaction uncoupling."…”

Preventive Effects of Vitamin C on Diethylnitrosamine-induced Hepatotoxicity in Smp30 Knockout Mice

“…It was reported that binucleated neuronal cells in the cortical region of the human brain in Alzheimer's disease showed severe oxidative stress (22,48). It was demonstrated that hepatocyte binucleation is induced by an increased production of ROS, reactive nitrogen species, and other free radicals, which cause significant oxidative DNA damage in hepatic cells (8,49,50). These results show that vitamin C might attenuate DEN-induced liver toxicity (Figure 4).…”

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro

“…In the current study, we observed both a reduction of proliferation (Figure 1) as well as of cell viability ( Figure S1), thus assuming that cell cycle arrest in HepG2 and Huh7.5 cells is possible. Other authors further implied that FB1 significantly influences the expression of cytochrome P450, which in turn influences important functional pathways of HCC in vitro [46]. Yet, since FB1 is a mycotoxin with a well-known promoting role in HCC in vivo [23], further data are needed in order to decipher its mechanistic role in HCC pathogenesis.…”