TY - JOUR T1 - Urinary Thiodiacetic Acid JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 508 LP - 515 VL - 25 IS - 4 AU - Lars W. Wormhoudt AU - Jan N. M. Commandeur AU - Jan H. T. M. Ploemen AU - Ruben S. Abdoelgafoer AU - Arman Makansi AU - Peter J. van Bladeren AU - Nico P. E. Vermeulen Y1 - 1997/04/01 UR - http://dmd.aspetjournals.org/content/25/4/508.abstract N2 - 1,2-Dibromoethane (1,2-DBE) is a carcinogenic compound that is metabolized both by cytochrome P450 (P450) and glutathioneS-transferase (GST) enzymes, and that has been used by us as a model compound to study interindividual variability in biotransformation reactions. In this study, the excretion of thiodiacetic acid (TDA) andS-(2-hydroxyethyl)-N-acetyl-l-cysteine (2-HEMA) were measured in the urine of rats dosed with 1,2-DBE, and experiments were performed to investigate to what extent P450 and GST enzymes contribute to the formation of TDA. To this end, CYP2E1, the main P450 isoenzyme catalyzing the oxidation of 1,2-DBE, was inhibited using disulfiram and diallylsulfide. Significant inhibition of CYP2E1, as confirmed by inhibition of the hydroxylation of chlorzoxazone, as well as inhibition of the formation of TDA from 1,2-DBE, was observed upon pretreatment of rats with these inhibitors, indicating that the P450-catalyzed oxidation of 1,2-DBE plays the major role in the TDA formation. No significant excretion of TDA was observed after administration of intermediate products of the GST pathway [i.e. S-(2-hydroxyethyl)glutathione and 2-HEMA], indicating that the GST-catalyzed metabolism of 1,2-DBE does not contribute to a significant extent to the formation of TDA. The results of this study show that TDA is specifically formed by P450 metabolites of 1,2-DBE, whereas the conjugation of 1,2-DBE to glutathione by GST enzymes does not contribute to the formation of TDA. TDA, excreted in urine, may thus be used as a biomarker of exposure to 1,2-DBE selectively reflecting the P450-catalyzed oxidation. In addition to 2-HEMA andS-[2-(N7-guanyl)ethyl]-N-acetyl-l-cysteine, TDA may be a valuable tool for biomonitoring and mechanistic studies into the metabolism and toxicity of 1,2-DBE. The American Society for Pharmacology and Experimental Therapeutics ER -