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725103 
Journal Article 
Modulation of Murine CYP2E1 Activity by Disulfiram on Trichloroethylene-Induced Neurotoxicity- A Pilot Study 
Harper, AA; Maher, TJ; Quang, LS; Shannon, MW; Woolf, AD 
2004 
1 
Journal of Toxicology: Clinical Toxicology
ISSN: 0731-3810
EISSN: 1097-9875 
42 
5 
753 
Objective: Trichloroethylene (TCE), a volatile organic solvent, is primarily metabolized through the cytochrome P450 system, principally the isoenzyme CYP2E1. Up to 1% of the general population have a genetic polymorphism in CYP2E1, which could contribute to an impaired metabolism of TCE. The purpose of this study was to investigate whether impaired CYP2E1 activity would alter TCE-induced neurobehavioral toxicity. Methods: Male B6C3F1 mice (n=5-10/group) were pretreated with the CYP2E1 inhibitor disulfiram 600 mg/kg intraperitoneal (i.p.) (dose based on our preliminary studies) or with vehicle alone. One hour later mice from both groups received incremental doses of TCE i.p. to complete dose-response curves. Two standard neurobehavioral outcome measures were used to assess the TD50 of TCE: the righting reflex and the rotarod test. Results: Pretreatment with disulfiram decreased the TD50 of TCE for the righting reflex from 3222 mg/kg (95% CI, 2971-3494 mg/kg) in control mice to 1261 mg/kg (95% CI, 966.2-1645 mg/kg) in pretreated mice (p < 0.0001). Pretreatment with disulfiram also decreased the TD50 of TCE for the rotarod test from 1720 mg/kg (95% CI, 1358-2133 mg/kg) in control mice to 703 mg/kg (95% CI, 437.7-1129 mg/kg) in pretreated mice (p < 0.0001). Conclusion: Pretreatment with disulfiram significantly increased the toxicity of TCE in mice. The presence of a genetic polymorphism in CYP2E1 could contribute to an unexpected tolerance or conversely an unexpected exaggerated toxic response to TCE exposure. Since disulfiram has actions other than CYP2E1 inhibition, further studies are needed to characterize more precisely the mechanisms underlying the effects on the TCE-induced toxicity observed in this study 
11/06/2007