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Adverse Effects and Intoxication with Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
However, the carcinogenic potency appears to be relatively low and dependent on the metabolism. Safrole is metabolically activated through the formation of intermediates, and these are able to directly react with DNA. Two bioactivation pathways of safrole to potentially hepatotoxic intermediates have been reported. One involves P450-catalyzed hydroxylation, thereby producing 1′-hydroxysafrole, and on further conjugation with sulfate, generating a reactive sulfate ester. This ester creates a highly reactive carbocation, which alkylates DNA. The second pathway involves P450-catalyzed hydroxylation of the methylenedioxy ring and finally formation of reactive p-quinone methide. Both pathways could explain the genotoxic effects of safrole. DNA adducts have been identified in vitro and in vivo (see Dietz and Bolton, 2005).
Molecular Imaging of Viable Cancer Cells
Published in Shoogo Ueno, Bioimaging, 2020
We further modified HMDER-βGal in order to achieve selective labeling of lacZ(+) cells with single-cell resolution in living tissues. For this purpose, we set out to integrate quinine methide chemistry into our design strategy. Quinone methide chemistry is widely used in the design of enzyme inhibitors, chromogenic substrates, activity-based probes, prodrugs, and for chemical selection of catalytic antibodies. We incorporated a fluoromethyl group as a leaving group at position 4 of HMDER-βGal to design SPiDER-βGal, so that the enzymatic reaction would produce a quinone methide intermediate, which is then trapped by intracellular nucleophiles, thus preventing diffusion of the activated fluorophore (Figure 2.5).33 SPiDER-βGal exhibited simultaneous activation of fluorescence and the ability to label intracellular components upon reaction with the enzyme, enabling selective and rapid detection of live lacZ(+) cells at single-cell resolution not only in culture, but also in live tissues.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Alternatively, tamoxifen undergoes O-dealkylation to give cis/trans-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene (also known as metabolite E), which is estrogenic and readily detected in plasma (Figure 3.96) (Langan-Fahey et al. 1990). Like 4-OH-tamoxifen, cis/trans-metabolite E can be activated to form DNA adducts by rat uterine peroxidases (Pathak et al. 1996). Metabolite E has been found in tamoxifen-resistant MCF-7 human breast tumors implanted in athymic nude mice, as well as in tumors from patients with clinical resistance (Wiebe et al. 1992), suggesting a potential role of metabolite E forms by local tissues in the development of tumor resistance to tamoxifen therapy. In addition, an estrogenic metabolite of tamoxifen, bisphenol, has been detected in these resistant tumors (Wiebe et al. 1992). Because of its structural similarity to 4-OH-tamoxifen, metabolite E could also be converted to a quinone methide, which has the potential to alkylate DNA and may contribute to the genotoxic effects of tamoxifen. Synthetic metabolite E quinone methide is stable with a half-life of 4 h under physiological conditions, and its half-life is approximately 4 min in the presence of reduced GSH (Fan and Bolton 2001). However, unlike the unstable GSH adducts of 4-OH-tamoxifen quinone methide, metabolite E GSH adducts are stable enough to be isolated and characterized by NMR and liquid chromatography mass spectrometry. Reaction of metabolite E quinone methide with DNA generated exclusively deoxyguanosine adducts (Fan and Bolton 2001).
Glutathione conjugation and protein modification resulting from metabolic activation of venlafaxine in vitro and in vivo
Published in Xenobiotica, 2021
Yilin Li, Yang Wang, Na Zhang, Shenzhi Zhou, Ying Peng, Jiang Zheng
Manganese dioxide was used to conduct biomimetic synthesis of quinone methide 5 from ODV. Quinone methides are known electrophilic species and easily react with thiols via Michael addition. The addition reactions may undergo two pathways, including 1,4-, and 1,6-addition (Damsten et al. 2008; Wen et al. 2014). 1,6-Addition is the most common. We speculated that the conjugation of quinone methide 5 with GSH or cysteine undergoes 1,6-addition. In other words, the sulphur was attached at benzylic carbon. To verify the carbon assignment, we brominated ODV by NBS, followed by reaction with GSH or cysteine. The bromination could take place at the benzylic carbon and on the phenyl ring. However, the sulfhydryl group can only react with the benzylic carbon by SN1 and/or SN2 reactions. The resulting GSH and cysteine conjugates showed the same retention times and mass spectral properties as those detected in the quinone methide 5-GSH/cysteine conjugation reaction mixtures (Figures 4 and 5). The findings supported the proposed 1,6-addition in the conjugation of quinone methide 5 with GSH or cysteine. Unfortunately, we were unable to gain enough amounts of the synthetic conjugates for NMR characterization, due to extremely low yields of the reactions. We speculated the low yields might result from steric hindrance which almost blocks the conjugation reactions. On the other hand, the formation of multiple by-products in the MnO2-mediated oxidation and bromination reactions was also an important factor for the low yields of the reactions. Despite this, the synthetic work via the two approaches allowed us to have the structure of GSH conjugate 6 and cysteine conjugate 7 elucidated.
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
Capsaicinoids (Figure 13(a)) are the principal pungent substances isolated from the dried fruits of chili peppers (Capsicum annum and Capsicum frutescens). There are six naturally occurring capsaicinoid analogs: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, nonivamide, homocapsaicin, and homodihydrocapsaicin. Capsaicin is the most abundant capsaicinoid, constituting approximately 60–70% of the total capsaicinoid content in hot pepper products (Reilly et al. 2001). Capsaicin has been used to treat various peripheral painful conditions such as rheumatoid arthritis and diabetic neuropathy, and the potential for dietary capsaicin to act as a chemopreventative agent is widely postulated (Bley et al. 2012). Both the vanilloid ring and a hydrophobic alkyl chain are required for optimal binding and activation of the capsaicin receptor TRPV1 to produce acute pain and cough as well as long-term analgesia (Sharma et al. 2013). Capsaicin undergoes a variety of oxidative reactions to form reactive quinoid species (Reilly et al. 2013). O-dealkylation of the methoxy group yields the catechol which is readily oxidized to an ortho-quinone (Figure 13(a)). Direct two electron oxidation of capsaicin gives a quinone methide. In addition, formation of the dimer 5,5′-dicapsaicin suggested that both CYP enzymes and HRP are capable of oxidizing capsaicin to free radical intermediates, for example, phenoxy radicals (Reilly et al. 2013). The O-demethylated GSH conjugate was the most abundant conjugate both in vitro and in vivo suggesting that CYP-mediated O-demethylation to the catechol followed by oxidations to ortho-quinone was the major bioactivation pathway (Reilly et al. 2013), It is likely that redox cycling of the ortho-quinones and/or free radicals contributed to capsaicin-induced oxidative damage to DNA and its potential carcinogenic properties (Oikawa et al. 2006).
Metabolic activation of deferiprone mediated by CYP2A6
Published in Xenobiotica, 2021
Xiaojiao Zheng, Xu Wang, Zifang Ding, Wei Li, Ying Peng, Jiang Zheng
Metabolic oxidation of M1 could also produce a p-quinone methide intermediate which can react with NAC and form a NAC conjugate with the same molecular weight as that of M3. If the quinone methide were generated, we would have obtained the NAC conjugate resulting from 1,4-addition at benzylic position. The NMR spectrum of M3 (Figure 4) excludes the possibility for the formation of such quinone methide intermediate, since NAC was found to attach on the aromatic ring of M3.