Oxidative Stress Due to ( R )-Styrene Oxide Exposure and The Role of Antioxidants in Non-Swiss Albino (NSA) Mice

Abstract

Styrene produces lung and liver damage that may be related to oxidative stress. The purpose of this study was to investigate the toxicity of (R)-styrene oxide (R-SO), the more active enantiomeric metabolite of styrene, and the protective properties of the antioxidants glutathione (GSH), N-acetylcysteine (NAC), and 4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF1) against R-SO-induced toxicity in non-Swiss Albino (NSA) mice. UPF1 is a synthetic GSH analog that was shown to have 60 times the ability to scavenge reactive oxygen species (ROS) in comparison to GSH. R-SO toxicity to the lung was measured by elevations in the activity 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. Antioxidants were not able to decrease the adverse effects of R-SO on lung. However, NAC (200 mg/kg) ip and GSH (600 mg/kg), administered orally prior to R-SO (300 mg/kg) ip, showed significant protection against liver toxicity as measured by SDH activity. Unexpectedly, a synthetic GSH analog, UPF1 (0.8 mg/kg), administered intravenously (iv) prior to R-SO, produced a synergistic effect with regard to liver and lung toxicity. Treatment with UPF1 (0.8 mg/kg) iv every other day for 1 wk for preconditioning prior to R-SO ip did not result in any protection against liver and lung toxicity, but rather enhanced the toxicity when administered prior R-SO. The results of the present study demonstrated protection against R-SO toxicity in liver but not lung by the administration of the antioxidants NAC and GSH.

Depletion by Styrene of Glutathione in Plasma and Bronchioalveolar Lavage Fluid of Non-Swiss Albino (NSA) Mice

“…While these amounts are high in comparison to human exposures (Miller et al, 1994;Cohen et al, 2002), they have been used in previous studies by us (Gadberry et al, 1996;Carlson, 1997;Carlson et al, 2006;Harvilchuck et al, 2008;Meszka-Jordan et al, 2009) and others (Chakrabarti et al, 1993). Because of the limited solubility of styrene and styrene oxide in water, corn oil was used as the vehicle, and controls received an equivalent volume (1 ml/ 100 g).…”

“…Styrene (600 mg/kg) was found to produce decreases in GSH levels in Clara cells (Harvilchuck & Carlson, 2006), the lung cell type that is the most active in styrene metabolism (Hynes et al, 1999). The emphasis on GSH depletion is important since the action of styrene may be related to the production of oxidative stress (Harvilchuck et al, 2008(Harvilchuck et al, , 2009Meszka-Jordan et al, 2009).…”

Metabolism and Toxicity of Styrene in Microsomal Epoxide Hydrolase-Deficient Mice

“…These doses have been used in previous studies by us (Gadberry et al, 1996;Carlson, 1997Carlson, , 2010Carlson et al, 2006;Harvilchuck et al, 2008Harvilchuck et al, , 2009Meszka-Jordan et al, 2009). However, toxicity required lowering of these doses to 200 and 150 mg/kg respectively.…”

“…In a second pathway, styrene oxide is conjugated with glutathione (GSH). The mechanism of styrene-induced toxicity is not completely clear but may be related to oxidative stress (Harvilchuck et al, 2008(Harvilchuck et al, , 2009Meszka-Jordan et al, 2009), since styrene produces significant decreases in GSH levels in liver and lung as well as in plasma and bronchioalveolar lavage fluid (Carlson, 2010). This may in part be related to the conjugation of styrene oxide with GSH.…”

Comparison of Styrene Oxide Enantiomers for Hepatotoxic and Pneumotoxic Effects in Microsomal Epoxide Hydrolase-Deficient Mice

“…Styrene oxide (SO) is detoxified by metabolism to styrene glycol by microsomal epoxide hydrolase (mEH, EPHX1). Styrene-induced toxicity may be related to oxidative stress (Harvilchuck et al, 2009;Meszka-Jordan et al, 2009) since styrene produces significant decreases in glutathione (GSH) levels in liver, lung (Turner The assistance of Scott Burchiel in supplying the mEH -/-breeding mice and technical assistance of Nancy Mantick are gratefully acknowledged. The research was supported in part by a gift and a grant from the Styrene Information and Research Center.…”