Effect of ethanol on the metabolism of trichloroethylene.
Trichloroethylene (TCE) is metabolized to chloral hydrate (CH) by the cytochrome P-450 monooxygenase system. CH can either be oxidized by chloral hydrate dehydrogenase to trichloroacetic acid (TCA) or reduced by alcohol dehydrogenase to trichloroethanol (TCEtOH). The oxidation reaction requires NAD+, while the reduction reaction requires NADH. Since ethanol (EtOH) is known to alter the NAD+/NADH ratio in the hepatocyte, it was coadministered with TCE in an attempt to alter the metabolism of TCE. This would provide a means for predicting interactions of ethanol on the hepatotoxicity and carcinogenicity of TCE. Male Sprague-Dawley rats were administered oral doses of either 1.52, 4.56, or 22.8 mmol/kg TCE, with the treatment group receiving an additional 1.52, 4.56, or 22.8 mmol/kg EtOH, respectively. Blood and urine samples were collected over 72 h. The clearance of TCE appeared to be saturated at the 4.56 mmol/kg dose, as evidenced by prolonged residence times for TCE in the body. Consistent with this result, there was an attenuation of the increases in the levels of TCEtOH and TCA in blood. However, the time to peak concentration of these metabolites was delayed with increasing doses and their residence time in the body was prolonged. Therefore, the area under the curve (AUC) for TCEtOH and TCA continued to increase with the higher doses of TCE. Measurement of the net output of these metabolites in urine confirmed that, although metabolism was saturated, the net metabolic conversion of TCE increased. As predicted, EtOH decreased blood levels of TCA, but only at early times at the high dose. EtOH did increase the urinary TCEtOH/TCA ratio at all dose levels. These results are consistent with the hypothesis of a more reduced state in the hepatocyte caused by the generation of excessive reducing equivalents by EtOH metabolism. The metabolism of TCE is shifted toward reduction to TCEtOH, away from oxidation to TCA. However, the effect was prominent only at extremely high doses of TCE and EtOH.
Larson
J L
JL
College of Pharmacy, Washington State University, Pullman.
Bull
R J
RJ
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014238:Trichloroacetic Acid / Q000378:metabolism; D014241:Trichloroethylene / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
C044588:1,1,2-trichloroethanol; D014241:Trichloroethylene; D000431:Ethanol; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin