Influence of the level of cytosolic epoxide hydrolase on the induction of sister chromatid exchanges by trans-beta-ethylstyrene 7,8-oxide in human lymphocytes.
trans-beta-Ethylstyrene 7,8-oxide, a substrate of cytosolic epoxide hydrolase, and 4-fluorochalcone oxide, an inhibitor of this enzyme, were investigated on induction of sister chromatid exchanges (SCE) in human lymphocytes. Both epoxides enhanced the frequency of SCE. 4-Fluorochalcone oxide at low concentration (2.5 microM) inhibited cytosolic epoxide hydrolase activity towards trans-beta-ethylstyrene 7,8-oxide in lymphocytes by 74% and had no effect on glutathione transferase activity using this substrate. At this concentration it did not induce SCE itself, but it potentiated the effect of trans-beta-ethylstyrene 7,8-oxide several fold. In lymphocytes from different subjects, the number of SCE induced by a low concentration of trans-beta-ethylstyrene 7,8-oxide correlated negatively with the individual cytosolic epoxide hydrolase activity (r = -0.72; -0.73 in two series of experiments). The number of SCE induced by a high concentration of trans-beta-ethylstyrene 7,8-oxide did not correlate with cytosolic epoxide hydrolase activity (r = 0.004; -0.24), but a negative correlation was found with glutathione transferase activity (r = -0.50). This finding is consistent with the results of biochemical studies in lymphocytes in which we determined the relative contribution of cytosolic epoxide hydrolase and glutathione transferase to the metabolism of trans-beta-ethylstyrene 7,8-oxide at varying substrate concentrations. The study demonstrates that the level of genotoxic effects induced in human lymphocytes is influenced by the individual level of detoxifying enzymes. At low concentrations, cytosolic epoxide hydrolase was more important than glutathione transferase activity.
Krämer
A
A
Institute of Toxicology, University of Mainz, Federal Republic of Germany.
Frank
H
H
Setiabudi
F
F
Oesch
F
F
Glatt
H
H
D002478:Cells, Cultured; D002599:Chalcone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D047188:Chalcones; D003600:Cytosol / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000187:drug effects / Q000378:metabolism*; D014644:Genetic Variation / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013343:Styrenes / Q000009:adverse effects* / Q000493:pharmacokinetics
D047188:Chalcones; D013343:Styrenes; C071863:4-fluorochalcone oxide; D002599:Chalcone; C027035:beta-ethylstyrene oxide; D004851:Epoxide Hydrolases; D005978:Glutathione