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


Oesch, Franz; Hengstler, Jan Georg; Arand, Michael (2004). Detoxication strategy of epoxide hydrolase-the basis for a novel threshold for definable genotoxic carcinogens. Nonlinearity in Biology, Toxicology, and Medicine, 2(1):21-26.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2004
Deposited On:22 Oct 2015 13:37
Last Modified:08 Dec 2017 14:27
Publisher:Taylor & Francis
ISSN:1540-1421
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1080/15401420490426963
PubMed ID:19330105

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