Evidence of Oxidative Stress and Associated DNA Damage, Increased Proliferative Drive, and Altered Gene Expression in Rat Liver Produced by the Cholangiocarcinogenic Agent Furan

Abstract

Furan is a potent cholangiocarcinogen in rat by an as yet undefined mechanism. The risk to man remains unclear. Using a time-course stop study design, we have investigated the potential of furan to induce oxidative stress and DNA damage associated with inflammatory and regenerative responses in rat liver. Furan was administered via oral gavage (30 mg/kg b.w. 5 daily doses per week), and livers were analyzed at time points between eight hr and three months. A one-month recovery group previously treated for three months was also included. There was a marked association between CYP2E1 expression and DNA oxidation (8-oxo-dG) in areas of centrilobular hepatocyte necrosis seen after a single dose. After one-month recovery from three-month treatment, 8-oxo-dG was still observed in areas of furan-induced cholangiofibrosis. Furan-induced changes in the expression of various genes associated with oxidative stress, DNA damage, and cell cycle control were identified during treatment and recovery. We propose that furan-induced cholangiocarcinomas emerge from areas of cholangiofibrosis as a result of a combination of chronic, persistent indirect damage to DNA through oxygen radicals coupled with persistent proliferative signals, including loss of connexin 32, that act to convert this DNA damage to fixed mutations.

Lycopene Protects the Diabetic Rat Kidney Against Oxidative Stress-mediated Oxidative Damage Induced by Furan

“…Enhanced MDA levels were reported also in furan toxicity by Selmanoğlu et al (Selmanoğlu et al 2012). Recent studies about furan showed the generation of ROS and stimulation of lipid peroxidation supporting the function of oxidative stress in furan toxicity Hickling et al 2010).…”

Furan-induced hepatotoxic and hematologic changes in diabetic rats: the protective role of lycopene

“…Recent in vivo studies in furan treated animals showed reactive oxygen species (ROS) formation and stimulation of lipid peroxidation (LPO) promoting the function of oxidative stress in the toxicity of furan (31,32). Furan-caused oxidative stress adds substantially to liver injury.…”

“…Furan-caused oxidative stress adds substantially to liver injury. Excessive ROS and raised LPO are some of the unwanted effects of furan (32). An increased MDA level, end product of LPO, is a major determinant of LPO (33).…”

Furan‐Oxidation‐Triggered Inducible DNA Cross‐Linking: Acyclic Versus Cyclic Furan‐Containing Building Blocks—On the Benefit of Restoring the Cyclic Sugar Backbone

“…[4][5][6] The study of its genotoxic effect and the underlying mechanism thereof continues to be an active area of interest and still needs to be completely understood. [7] Notwithstanding these toxic effects, furan has been identified as representing a caged reactive functionality and seems to be an ideal template for the mild and selective generation of a reactive intermediate on demand. This furan-ring oxidation principle and the idea of using an easily incorporated and stable aromatic furan moiety as a substitute for a reactive unit has been elegantly used in the total synthesis of macrosphelides A and B [8] and (+)-Aspicillin.…”