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724859 
Journal Article 
Cytochrome P450 2E1 (CYP2E1) Induction By Pyridazine Produces Qualitative And Quantitative Changes In The Metabolism Of Trichloroethylene To Potentially Carcinogenic Metabolites 
Lee, S; Muralidhara, S; White, CA; Bruckner, JV 
2005 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
TOX/5000863 
84 
1-S 
149 
English 
CYP2E1, an isozyme of cytochrome P450, is expressed mainly in the liver. It is inducible by a variety of xenobiotic compounds such as ethanol, acetone and aspirin. CYP2E1 catalyzes the oxidation of many small and hydrophobic volatile organic chemicals (VOCs), including trichloroethylene (TCE). It is generally accepted that CYP2E1 induction will result in increased production of metabolites from TCE, and an attendant increase in cancer risk. The objective of the current study was to investigate the influence of CYP2E1 induction by pyridazine (PZ) on TCE oxidation as well as its subsequent effects on downstream metabolites that have been implicated in hepatocarcinogenesis. Groups of 6 male Sprague-Dawley rats of 175 g body weight were gavaged with a series of doses of TCE up to 200 mg/kg. Other groups of 6 animals were induced with PZ (200 mg/kg, ip) for 3 days before being challenged with TCE 24 hrs after the last PZ dose. Serial blood samples were collected for up to 24 or 48 hrs via an indwelling carotid artery catheter. TCE and its major metabolites were analyzed in the headspace of the micro blood samples by gas chromatography. TCE Cmax values were substantially lower in the induced animals, reflecting increased first-pass hepatic elimination of TCE. The PZ-dosed animals had higher trichloroethanol (TCOH) AUCs, but markedly lower trichloroacetic acid (TCA) AUCs, when compared to those of uninduced rats. Dichloroacetic acid (DCA) levels, which were barely detectable blood in uninduced rats, were prominent in induced groups, suggesting increased conversion of TCA to DCA. Whereas, chloral hydrate (CH) levels were unaffected by PZ, but TCOH formation appeared to be favored over TCA. Additional work will be needed to determine whether CYP2E1 induction is of consequence with very low TCE exposure levels 
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