Detoxication strategy of epoxide hydrolase-the basis for a novel threshold for definable genotoxic carcinogens

Nonlinearity Biol Toxicol Med. 2004 Jan;2(1):21-6. doi: 10.1080/15401420490426963.


From our recent work on the three-dimensional structure of epoxide hydrolases we theoretically deduced the likelihood of a two-step catalytic mechanism that we and others have subsequently experimentally confirmed. Analysis of the rate of the two steps by us and by others show that the first step-responsible for removal of the reactive epoxide from the system-works extraordinarily fast (typically three orders of magnitude faster than the second step), sucking up the epoxide like a sponge. Regeneration of the free enzyme (the second step of the catalytic mechanism) is slow. This becomes a toxicological problem only at doses of the epoxide that titrate the enzyme out. Our genotoxicity work shows that indeed this generates a practical threshold below which no genotoxicity is observed. This shows that-contrary to old dogma-practical thresholds exist for definable genotoxic carcinogens.

Keywords: DNA damage; V79 Chinese hamster lung fibroblasts; epoxide hydrolase; epoxy compounds metabolism; ester intermediate; genotoxicity.