Lee, S; White, CA; Muralidhara, S; Anand, SS; Bruckner, JV
CYP2E1, which catalyzes the oxidation of many small volatile organic chemicals such as TCE, is induced by a variety of xenobiotics (i.e., ethanol, acetone and aspirin), as well as by certain diseases (i.e., obesity and diabetes). CYP2E1 induction results in increased production of metabolites from TCE, leading to the potential for increased cancer risks. Trichloroacetic acid (TCA) is generally believed to be the mouse proximate hepatocarcinogenic metabolite of TCE. The objective of this study is to investigate the effect of CYP2E1 induction on TCE's metabolic profile, including the toxicokinetics (TKs) of downstream metabolites, TCA, chloral hydrate (CH) and trichloroethanol (TCOH). Young male Sprague-Dawley rats (n = 5, 175 g) were given PZ (200 mg/kg, ip) in saline or saline (controls) daily for 3 days. Animals received TCE (200, 50 and 10 mg/kg, po), TCOH (50 mg/kg, iv) or TCA (50 mg/kg, iv). TCE, CH, TCOH and TCA in collected blood and urine were analyzed by head-space GC. TK parameters of TCE, CH, TCOH and TCA were determined using WinNonlin. The most prominent effects by PZ were on TKs of TCA. When TCA was dosed, half-life (T1/2) was decreased significantly [control: 799 vs. PZ-induced: 248 min] and TCA clearance (CL) was increased 3.2-fold by PZ. No change in the volume of distribution was noted. After TCOH administration, TKs of TCA were not different from those observed after TCA dosing. However, after TCE administration, TCA T1/2 in controls was significantly longer (3299 min) as compared to TCA dosing indicating that TCA is a formation-rate limited metabolite. TCE dosed induced animals had similar TCA T1/2s as compared to those observed for TCA after TCOH or TCA dosing. This suggests that PZ enhances systemic clearance of TCA. More rapid clearance of the TCA may, in fact, be beneficial in that liver cancer risk from TCE would be reduced
analogs & Animals; biosynthesis; blood; Cytochrome P-450 CYP2E1; derivatives; Enzyme Induction; Ethylene Chlorohydrin; Liver; Male; metabolism; Organic Chemicals; pharmacokinetics; Pyridazines; Rats; Rats,Sprague-Dawley; Research Support,U.S.Gov't,Non-P.H.S.; toxicity; TOXLINE 07/14/08 to 03/03/09; Trichloroacetic Acid; Trichloroethylene; urine
