Detoxication Strategy of Epoxide Hydrolase—The Basis for a Novel Threshold for Definable Genotoxic Carcinogens

Oesch, Franz; Hengstler, Jan G.; Arand, Michael

doi:10.1080/15401420490426963

Cited by 13 publications

(6 citation statements)

References 19 publications

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“…Epoxides are highly reactive compounds with an electrophilic functional group. This electrophilic group allows the epoxide to react with electron-rich moieties in the DNA and produce DNA adducts or DNA strand breaks [ 39 ]. Styrene, for example, can be activated to a genotoxic intermediate in the human body.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity and Genotoxicity Assessment of Sandalwood Essential Oil in Human Breast Cell Lines MCF‐7 and MCF‐10A

Ortíz

Morales

Sastre

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Sandalwood essential oil (SEO) is extracted from Santalum trees. Although α-santalol, a main constituent of SEO, has been studied as a chemopreventive agent, the genotoxic activity of the whole oil in human breast cell lines is still unknown. The main objective of this study was to assess the cytotoxic and genotoxic effects of SEO in breast adenocarcinoma (MCF-7) and nontumorigenic breast epithelial (MCF-10A) cells. Proteins associated with SEO genotoxicity were identified using a proteomics approach. Commercially available, high-purity, GC/MS characterized SEO was used to perform the experiments. The main constituents reported in the oil were (Z)-α-santalol (25.34%), (Z)-nuciferol (18.34%), (E)-β-santalol (10.97%), and (E)-nuciferol (10.46%). Upon exposure to SEO (2–8 μg/mL) for 24 hours, cell proliferation was determined by the MTT assay. Alkaline and neutral comet assays were used to assess genotoxicity. SEO exposure induced single- and double-strand breaks selectively in the DNA of MCF-7 cells. Quantitative LC/MS-based proteomics allowed identification of candidate proteins involved in this response: Ku70 (p = 1.37E − 2), Ku80 (p = 5.8E − 3), EPHX1 (p = 3.3E − 3), and 14-3-3ζ (p = 4.0E − 4). These results provide the first evidence that SEO is genotoxic and capable of inducing DNA single- and double-strand breaks in MCF-7 cells.

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Section: Discussionmentioning

confidence: 99%

Cytotoxicity and Genotoxicity Assessment of Sandalwood Essential Oil in Human Breast Cell Lines MCF‐7 and MCF‐10A

Ortíz

Morales

Sastre

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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“…Under neutral physiological conditions, attack by such nucleophiles is expected to take place primarily via an S N 2 pathway at the less hindered, β-carbon atom, that is, the least substituted carbon, 1° > 2° > 3°. − However, a competing S N 1 mechanism at the α-carbon has been suggested to occur in a some cases, such as for epoxides with a vicinal aromatic group . In addition to ring opening by biological nucleophiles, epoxides can undergo hydrolysis facilitated by epoxide hydrolase (EH) . Epoxides that are poor EH substrates tend to be highly carcinogenic .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to ring opening by biological nucleophiles, epoxides can undergo hydrolysis facilitated by epoxide hydrolase (EH) . Epoxides that are poor EH substrates tend to be highly carcinogenic . Finally, in vitro studies have shown that some epoxides can undergo intramolecular rearrangement to aldehydes (Scheme ); however, it is not clear whether these thermal rearrangements occur in vivo. , …”

Section: Introductionmentioning

confidence: 99%

A Free Energy Approach to the Prediction of Olefin and Epoxide Mutagenicity and Carcinogenicity

Kostal

Voutchkova‐Kostal

Weeks

et al. 2012

Chem. Res. Toxicol.

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The mutagenic and carcinogenic effects of strong alkylating agents, such as epoxides, have been attributed to their ability to covalently bind DNA in vivo. Most olefins are readily oxidized to reactive epoxides by CytP450. In an effort to develop predictive models for olefin and epoxide mutagenicity, the ring openings of 15 halogen-, alkyl-, alkenyl-, and aryl-substituted epoxides were modeled by quantum-mechanical transition state calculations using MP2/6-31+G(d,p) in the gas phase and in aqueous solution. Free energies of activation (ΔG(‡)) and free energies of reaction (ΔG(rxn)) were computed for each epoxide in the series. This study finds that an aqueous solution ΔG(rxn) threshold value of approximately -14.7 kcal/mol can be used to discern mutagenic/carcinogenic epoxides (ΔG(rxn) < -14.7 kcal/mol) from nonmutagens/noncarcinogens (ΔG(rxn) > -14.7 kcal/mol). The computed reaction thermodynamics are appropriate regardless of ring-opening mechanism in vivo and are thus proposed as an effective in silico screen and design guideline for decreasing potential mutagenicity and carcinogenicity of olefins and their respective epoxides.

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“…Oesch et al (2000Oesch et al ( , 2004 demonstrated that the efficiency of the EH-mediated hydrolysis of epoxides was underestimated based on the observed overall rate of dihydrodiol formation. In fact, epoxides are rapidly trapped by forming covalent ester intermediates (E-I) without any significant formation of dihydrodiol.…”

mentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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Oxetane moieties are increasingly being used by the pharmaceutical industry as building blocks in drug candidates because of their pronounced ability to improve physicochemical parameters and metabolic stability of drug candidates. The enzymes that catalyze the biotransformation of the oxetane moiety are, however, not well studied. The in vitro metabolism of a spiro oxetane-containing compound AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] was studied and one of its metabolites, M1, attracted our interest because its formation was NAD(P)H independent. The focus of this work was to elucidate the structure of M1 and to understand the mechanism(s) of its formation. We established that M1 was formed via hydration and ring opening of the oxetanyl moiety of AZD1979. Incubations of AZD1979 using various human liver subcellular fractions revealed that the hydration reaction leading to M1 occurred mainly in the microsomal fraction. The underlying mechanism as a hydration, rather than an oxidation reaction, was supported by the incorporation of 18 O from H 2 18O into M1. Enzyme kinetics were performed probing the formation of M1 in human liver microsomes. The formation of M1 was substantially inhibited by progabide, a microsomal epoxide hydrolase inhibitor, but not by trans-4-[4-(1-adamantylcarbamoylamino)cyclohexyloxy]-benzoic acid, a soluble epoxide hydrolase inhibitor. On the basis of these results, we propose that microsomal epoxide hydrolase catalyzes the formation of M1. The substrate specificity of microsomal epoxide hydrolase should therefore be expanded to include not only epoxides but also the oxetanyl ring system present in AZD1979.

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Detoxication Strategy of Epoxide Hydrolase—The Basis for a Novel Threshold for Definable Genotoxic Carcinogens

Cited by 13 publications

References 19 publications

Cytotoxicity and Genotoxicity Assessment of Sandalwood Essential Oil in Human Breast Cell Lines MCF‐7 and MCF‐10A

Cytotoxicity and Genotoxicity Assessment of Sandalwood Essential Oil in Human Breast Cell Lines MCF‐7 and MCF‐10A

A Free Energy Approach to the Prediction of Olefin and Epoxide Mutagenicity and Carcinogenicity

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

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