Print Email Facebook Twitter Inter-individual variability in the oxidation of 1,2-dibromoethane: Use of heterologously expressed human cytochrome P450 and human liver microsomes Title Inter-individual variability in the oxidation of 1,2-dibromoethane: Use of heterologously expressed human cytochrome P450 and human liver microsomes Author Wormhoudt, L.W. Ploemen, J.H.T.M. de Waziers, I. Commandeur, J.N.M. Beaune, P.H. van Bladeren, P.J. Vermeulen, N.P.E. Instituut CIVO-Toxicologie en Voeding TNO Publication year 1996 Abstract 1,2-Dibromoethane (1,2-DBE) is mainly used as an additive in leaded gasoline and as a soil fumigant and it is a suspected carcinogen in humans. In this study, the oxidative bioactivation of 1,2-DBE to 2-bromoacetaldehyde (2-BA) was studied using heterologously expressed human cytochrome P450 (P450) isoenzymes and human liver microsomes. Out of ten heterologously expressed human P450 isoenzymes (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP2C8, CYP2C9, CYP2C18, CYP3A4 and CYP3A5), only human CYP2A6, CYP2B6 and CYP2E1 metabolized 1,2-DBE, albeit with strongly differing catalytic efficiencies. The apparent K(m) and V(max) values were 3.3 mM and 0.17 pmol/min per pmol P450 for CYP2A6, 9.7 mM and 3.18 pmol/min per pmol P450 for CYP2B6 and 42 μM and 1.3 pmol/min per pmol P450 for CYP2E1, respectively. In all of 21 human liver samples studied, 1,2-DBE was oxidized with activities ranging from 22.2 to 1027.6 pmol/min per mg protein, thus showing a 46-fold inter-individual variability. The kinetics of the oxidative metabolism of 1,2-DBE to 2-BA in human liver microsomes were linear, indicating the involvement of primarily one single P450 isoenzyme. There was a tendency towards a positive correlation between the oxidative metabolism of 1,2-DBE in the human liver microsomes and the 6-hydroxylation of chlorzoxazone, a selective substrate for CYPE1. Furthermore, the oxidative metabolism of 1,2-DBE was inhibited by the specific CYP2E1 inhibitors disulfiram (DS) and diethyldithiocarbamate (DDC). In contrast, a poor correlation was found between the immunochemically quantified amount of CYP2E1 and the microsomal chlorzoxazone 6-hydroxylation or the 1,2-DBE oxidation. The results indicate that CYP2E1 is probably the major P450 isoenzyme involved in the oxidative hepatic metabolism of 1,2-DBE in humans. The inter-individual variability in the oxidative bioactivation of 1,2-DBE in humans, largely due to inter-individual variability in the catalytic activity of hepatic CYP2E1, may have important consequences for the risk assessment for human exposure to 1,2-DBE. Chemicals/CAS: Acetaldehyde, 75-07-0; bromoacetaldehyde, 17157-48-1; Carcinogens; Cytochrome P-450 Enzyme System, 9035-51-2; Ethylene Dibromide, 106-93-4; Isoenzymes Subject AcetaldehydeCarcinogensCytochrome P-450 Enzyme SystemEthylene DibromideHumansHydroxylationIsoenzymesKineticsMicrosomes, LiverOxidation-ReductionStructure-Activity Relationship To reference this document use: http://resolver.tudelft.nl/uuid:1d433bf6-50cc-4ce8-a63f-500e20ef369d DOI https://doi.org/10.1016/0009-2797(96)03723-4 TNO identifier 233458 ISSN 0009-2797 Source Chemico-Biological Interactions, 101 (3), 175-192 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.