Oxidative stress due to styrene and styrene oxide exposure and the role of antioxidants
Abstract
The purpose of this study was to investigate the role of oxidative stress in styrene or styrene oxide toxicity and the protective properties of the following antioxidants, glutathione (GSH), N-acetylcysteine (NAC), 4-methoxy-L-tyrosinyl-γ-L-glutamyl-L-cysteinyl-glycine (UPF1), and D-serinyl-γ-L-glutamyl-L-cysteinyl-glycine (UPF6) against GSH depletion in tissue as well as styrene or styrene oxide-induced toxicity. UPF1 is a synthetic GSH analog that has been shown to have 60 times the ability to scavenge reactive oxygen species (ROS) in comparison to GSH. Liver and lung toxicity due to styrene has been studied extensively. Previous studies demonstrated that the bioactivated metabolite of styrene, styrene-7,8-oxide, is more potent than styrene itself. In the present study, styrene toxicity to the lung was measured by elevations in the release of lactate dehydrogenase (LDH), protein concentration, and number of cells in bronchoalveolar lavage fluid (BALF). Toxicity to the liver was measured by increases in serum sorbitol dehydrogenase (SDH) activity. Two strains of mice were used in this study, CD-1 and Non-Swiss Albino (NSA) mice. GSH levels in liver and lung were measured by the GSH-DTNB method after antioxidant preconditioning by NAC (200 mg/kg) intraperitoneal (i.p.) or GSH (300 mg/kg or 600 mg/kg) orally. The toxicity of styrene in liver and lung was measured as well as the effect of antioxidants in the protection against this toxicity. Administration of antioxidants GSH or NAC was not sufficient to elevate GSH levels in lung and liver tissues. Styrene alone caused a significant depletion of GSH in liver and lung. Neither GSH nor NAC was able to prevent this depletion. Most of the antioxidants were not able to decrease the toxic effects of styrene or styrene oxide on liver or lung. However, NAC (200 mg/kg) i.p. and GSH (600 mg/kg) oral administration prior to R-SO showed significant protection against liver toxicity measured by SDH activity. Unexpectedly, a synthetic GSH analog, UPF1 (0.8 mg/kg), administered intravenously (i.v.) prior to (R)-styrene oxide caused a synergistic effect with regard to liver and lung toxicity. UPF6 (0.8 mg/kg) i.v. administration produced similar results. One week UPF1 (0.8 mg/kg) i.v. preconditioning prior to styrene or R-SO i.p. did not result in any protection against liver and lung toxicity, but rather enhanced the toxicity when administered prior to styrene or R-SO. The results of the present study confirmed GSH depletion in tissues due to styrene exposure. However, there is no evidence for protection against styrene or styrene oxide toxicity in liver or lung by the administration of antioxidants with the exception of NAC and GSH on liver toxicity.
Degree
M.S.
Advisors
Carlson, Purdue University.
Subject Area
Toxicology|Surgery
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.