Alterations in toxicokinetics of trichloroethylene (TCE) and trichloroacetic acid (TCA) due to cytochrome P450 2E1 (CYP2E1) induction
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Trichloroethylene (TCE) is a chlorinated solvent used primarily as a degreaser. It has been reported that TCE produced elevated incidences of tumors in rodents by both the oral and inhalation routes of exposure. There is limited evidence to support TCE as a cause of cancer in humans. Trichloroacetatic acid (TCA) is of considerableinterest to the scientific and regulatory communities, since it is a toxicologically important metabolite of TCE and perchloroethylene (PERC), as well as one of the byproducts of drinking water chlorination. TCA is generally believed to be the proximate hepatocarcinogenic metabolite of TCE in mice. CYP2E1, which catalyzes the oxidation of many small volatile organic chemicals, is responsible for the first step of TCE oxidation. CYP2E1 is induced by a variety of xenobiotics (i.e., ethanol, acetone and aspirin), as well as by certain conditions and diseases (i.e., obesity, alcoholism and diabetes). Thus, induction of CYP2E1 is generally expected to cause a significant increase in the biotransformation of highly metabolized compounds, such as TCE, possibly leading to an increase in cancer risks. Low-level TCE exposure scenarios have not received much attention. Information on the carcinogenic responses to TCE and its metabolites has been obtained at very high doses, which have been used to predict cancer risks of low-level TCE exposure by linear extrapolation. Thus, the main objective was to investigate changes in the metabolism of low doses of TCE and on the pharmacokinetics of downstream metabolites (especially TCA), due to CYP2E1 induction by pyridazine (PZ) as a inducer. The most prominent effects of CYP2E1 induction were on the toxicokinetic profiles of TCA. The data suggest that CYP2E1 induction enhances systemic and renal clearance of TCA, possibly by affecting organic anion transporters/multidrug resistance-relatedprotein (OATs/MRPs) in the kidneys. So, future investigation of OATs/MRPs should provide a better understanding of the urinary elimination mechanism of small organic acids such as TCA. Rapid clearance of the TCA may, in fact, be beneficial in that liver cancer risk from TCE would be reduced.