Oesch Franz, Hengstler Jan Georg, Arand Michael
Institute of Toxicology, University of Mainz, Mainz, Germany.
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.
基于我们最近对环氧水解酶三维结构的研究工作，我们从理论上推断出一种两步催化机制的可能性，随后我们和其他人通过实验证实了这一机制。我们和其他人对这两步反应速率的分析表明，第一步负责从系统中去除活性环氧化物，其反应速度极快（通常比第二步快三个数量级），就像海绵吸水一样吸收环氧化物。游离酶的再生（催化机制的第二步）则较慢。只有在环氧化物剂量能够耗尽酶时，这才会成为一个毒理学问题。我们的遗传毒性研究表明，确实存在一个实际阈值，低于该阈值则未观察到遗传毒性。这表明，与过去的教条相反，可定义的遗传毒性致癌物存在实际阈值。
