General toxicology
Timbrell John in Study Toxicology Through Questions, 2017
(d) The NIH shift is the term used to describe the chemical rearrangement which occurs during the cytochrome P450 mediated oxidation of aromatic compounds. The rearrangement was discovered at and reported by workers from the National Institutes of Health (NIH) in the U.S.A., hence the name. The phenomenon can best be illustrated in the oxidation of naphthalene (see figure page 51). When naphthalene is labelled with a deuterium atom at position 1 , the products of cytochrome P450 mediated oxidation are 1- and 2-naphthols. In both products some deuterium is lost, but in the 1-naphthol product deuterium is found to have moved to the 2 position. In the 2-naphthol, some deuterium is replaced by hydrogen. This indicates that an epoxide intermediate is formed. The ratio of hydrogen to deuterium in the products and the ratio of 1-naphthol to 2-naphthol reflect the isotope effect of deuterium and are consistent with the postulated mechanism as shown in the figure below.
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Haloalkenes are bioactivated by P450-mediated oxidation of the vinyl moiety. Oxidation of vinyl chloride or vinyl bromide yields the ultimate carcinogenic electrophiles, vinyl halogen oxides. These intermediates can nonenzymatically form an additional electrophile haloacetaldehyde, epoxides or covalently bind heme, and inactivate P450. Detoxification reactions include hydration of the vinyl halogen oxide by epoxide hydrolase and reduction of the haloacetaldehyde by aldehyde and alcohol dehydrogenases. CYP2B is the P450 subfamily most active for catalyzing epoxide formation from vinyl chloride and vinyl bromide. P450-generated acyl halides and haloaldehydes are also bioactivation intermediates in the biotransformation pathways for structurally related vinylidene chloride and trichloroethylene. The haloacetaldehyde is the major electrophilic metabolite. An oxygenated intermediate from P450 oxidation leads to nonenzymatic formation of a haloaldehyde or an epoxide or to P450 inactivation by heme alkylation. Epoxides are relatively minor bioactivation products. For vinylidene chloride, both CYP2A and CYP2B are most active for oxidation and most susceptible to inactivation.
Overview of the Biotransformation of Antiepileptic Drugs
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
Once epoxides are formed by mixed-function oxidases, several things can happen to them. One, they can be hydrolyzed enzymatically to dihydrodiols. The enzyme responsible for the hydration is epoxide hydrolase. This enzyme is located predominantly in liver microsomes, but it is also found in hepatic cell cytosol.11 The microsomal hydrolase is inducible by many xenobiotics, and it possibly exists in multiple forms. Second, the epoxide can rearrange nonenzymatically to form phenols or dihydrodiols. Third, the epoxide can interact with glutathione (see below). Fourth, the epoxide may ultimately react with tissues. The tissue-epoxide interaction can be the source of important drug toxicity, e.g., tissue necrosis or carcinogenesis. Just which route of biotransformation a given drug takes depends on many factors, not the least of which is its chemical structure.
Association of Activity Altering Genotypes - Tyr113His and His139Arg in Microsomal Epoxide Hydrolase Enzyme with Esophageal Squamous Cell Carcinoma
Published in Nutrition and Cancer, 2019
Sumaiya Nabi, Gulzar Ahmad Bhat, Beenish Iqbal, Mohd Maqbool Lone, Ghulam Nabi Lone, Maroof Ahmad Khan, Nazir Ahmad Dar
The enhanced risk of ESCC in presence of mEH exon 3 slow genotype and predicted low mEH activity in our study is consistent with results obtained from previous studies on ESCC (38,41) and cancers occurring in colon (35), liver (49), and lung (33) which supports a strong detoxification role for mEH. In vitro data (27) suggests exon 3 slow genotype confer lower enzyme activity by altering protein stability. Also, the combined His113His + His139His genotype (variant) depicting low enzyme activity tends to exhibit a shorter protein half-life than the remaining variants (28). Individuals with lower activity enzyme may have decreased ability to detoxify the genotoxic epoxides and their derivatives and consequently exhibits increased susceptibility to various cancers. It is pertinent to mention the significant role of slow genotype (His 113/His113) in human sensitivity to the genotoxic and carcinogenic effects of epoxide derivatives of 1,3 butadiene (50). Epoxides and its derivatives, known human carcinogens (51) are usually present in the diet or generated within the body from dietary PAHs and nitrosamines or from benzo(a)pyrene/1,3 butadiene present in cigarette smoke or via occupational settings. Hence, hydrolysis by mEH plays a pivotal role in detoxification and thus protection of macromolecules from the electrophilic attack of typically unstable and reactive epoxides and its intermediates.
Characterisation of peppermint (Mentha piperita L.) essential oil encapsulates
Published in Journal of Microencapsulation, 2019
Murat Yilmaztekin, Steva Lević, Ana Kalušević, Mustafa Cam, Branko Bugarski, Vesna Rakić, Vladimir Pavlović, Viktor Nedović
Thermal stability of free and encapsulated peppermint essential oil was investigated by thermogravimetry and results are presented in Figure 3. Free peppermint essential oil shows first mass loss in the temperature region 90–200 °C (∼50% of mass loss). In the second temperature region, between 200 and 300 °C up to ∼60% of essential oil evaporates. The two steps in the TGA thermogram are most probably result of different boiling points of essential oil compounds. Also, it could be expected that some essential oil compounds are thermally decomposed to the new compounds. According to Neuenschwander et al. (2010), α-pinene autoxidation under elevated temperature leads to the formation of different types of peroxyl radicals. Further, peroxyl radicals’ reaction leads to the production of hydroperoxide or epoxide and alkoxyl radicals.
Association between EPHX1 polymorphism rs1051740 and the risk of ovarian cancer: a meta-analysis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Ying Jin
Epoxide hydrolase 1 (EPHX1) is an important phase II biotransformation enzyme in vivo, and plays a significant role in the activation and detoxification of toxins [10]. Generally, epoxides are regarded as the most toxicologically active form of drugs or environmental chemicals [11], while EPHX1 can promote the hydrolysis of epoxides into trans-dihydrodiols [12]. EPHX1 gene, coding for this enzyme, is located at chromosome 1q42.1 with 20271 base-pairs, and is composed of 9 exons and 8 introns [13]. In this gene, more than 10 single nucleotide polymorphisms (SNPs) have been identified. Among them, the polymorphism rs1051740 leading to the substitution of tyrosine to histidine at exon 3 has been reported to reduce the enzyme activity by more than 40% in vitro [14]. Considering the role of EPHX1 in response to exogenous toxins, this polymorphism of the gene EPHX1 has been proposed to be related to the risk of multiple cancers, including ovarian cancer [15], hepatocellular carcinoma [13] and colorectal cancer [14].
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