Abstract

 
 
 
 Purpose: To determine the effect of the glutathione (GSH) suppressors styrene oxide (SO) and diethyl maleate (DEM) on the hepatic expression of cytochrome P450 family 1 (Cyp1) isoforms that are related to carcinogenesis including Cyp1a1, Cyp1a2, and Cyp1b1.
 Methods: Seven-week-old ICR mice were intraperitoneally injected with SO (150 and 300 mg/kg/day), DEM (175 and 350 mg/kg/day), or N-acetylcysteine (NAC; 300 and 600 mg/kg/day) for 7, 14, or 28 days. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic Cyp1 expression, total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were determined.
 Results: ALT and AST levels were markedly increased by SO and DEM while GSH/GSSG ratio was decreased by SO in all treatments (p < 0.05), while high dose (350 mg/kg/day) DEM significantly suppressed GSH/GSSG ratio at 28 days (p < 0.05). The expressions of Cyp1a1, Cyp1a2, and Cyp1b1 were induced by SO and DEM, corresponding with induction of ethoxy/methoxy-resorufin O- dealkylase activities.
 Conclusion: The Cyp1 family metabolizes procarcinogens to carcinogenic DNA adducts; exposure to the industrial solvents, SO and DEM, raises the risk of carcinogenesis via GSH depletion coupled with Cyp1 induction.
 
 
 
Highlights
A wide array of xenobiotics can cause cellular damage and affect cellular protective systems depending on their concentrations and the period of exposure
For long term treatment (28 days), neither diethyl maleate (DEM) nor NAC changed ALT or AST levels, while both enzyme levels were increased by styrene oxide (SO). These results reveal that SO and DEM caused hepatotoxicity, while NAC exerted hepato-protective effect after 14-days of treatment by reducing ALT levels
For the long-term treatment of 28 days, SO and DEM significantly induced expressions of Cyp1a1 (Figure 3 A), Cyp1a2 (Figure 3 B), and Cyp1b1 (Figure 3 C) mRNA, which corresponded with increased Ethoxyresorufin O-deethylase (EROD) (Figure 3 D) and MROD (Figure 3 E) activities
Summary
A wide array of xenobiotics can cause cellular damage and affect cellular protective systems depending on their concentrations and the period of exposure. Glutathione (GSH) is a stably controlled antioxidant that is present both intracellularly and extracellularly [1]. Some chemicals such as diethyl maleate (DEM), carbon tetrachloride, acetaminophen, and chloroform are metabolized to mercapturic acid derivatives, which are detoxified by GSH. Glutathione-S-transferase leading to GSH depletion in tissue stores [2]. Disruption of the oxidative protective system, such as depletion of GSH stores, affects the metabolism of xenobiotics. We investigated the effect of GSH depletion on the expression of the carcinogenesis-associated CYP 1 isoforms, Cyp1a1, Cyp1a2, and Cyp1b, in mouse livers. The supernatants were analyzed for GSH or GSSG content using 5,5 -dithiobis (2nitrobenzoic acid) thiol formation. The data are presented as mean S.D. and were analyzed using one-way ANOVA followed by Tukey post hoc test (IBM SPSS statistics version 23, Armonk, NY). p < 0.05 was considered statistically significant
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