INTERINDIVIDUAL VARIABILITY IN THE OXIDATION OF 1,2-DIBROMOETHANE - USE OF HETEROLOGOUSLY EXPRESSED HUMAN CYTOCHROME-P450 AND HUMAN LIVER-MICROSOMES

1,2-Dibromoethane (1,2-DBE) is mainly used as an additive in leaded ga soline and as a soil fumigant and it is a suspected carcinogen in huma ns. In this study, the oxidative bioactivation of 1,2-DBE to 2-bromoac etaldehyde (2-BA) was studied using heterologously expressed human cyt ochrome 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 hu man CYP2A6, CYP2B6 and CYP2E1 metabolized 1,2-DBE, albeit with strongl y 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 3.1 8 pmol/min per pmol P450 for CYP2B6 and 42 mu M and 1.3 pmol/min per p mol P450 for CYP2E1, respectively. In all of 21 human liver samples st udied. 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 var iability. The kinetics of the oxidative metabolism of 1,2-DBE to 2-BA in human liver microsomes were linear, indicating the involvement of p rimarily one single P450 isoenzyme. There was a tendency towards a pos itive correlation between the oxidative metabolism of 1,2-DBE in the h uman liver microsomes and the 6-hydroxylation of chlorzoxazone, a sele ctive substrate for CYP2E1. 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 th e microsomal chlorzoxazone 6-hydroxylation or the 1,2-DBE oxidation. T he results indicate that CYP2E1 is probably the major P450 isoenzyme i nvolved 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 catalyt ic activity of hepatic CYP2E1, may have important consequences for the risk assessment for human exposure to 1,2-DBE.