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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Epoxide functionalities are similar to aziridines in their ability to alkylate DNA. Although some carcinogens, such as the aflatoxins, are known to alkylate DNA via an epoxide moiety, there are currently no anticancer agents in clinical use that contain preformed epoxide moieties. However, treosulfan (L-threitol 1,4-bismethanesulfonate, OvastatTM, TrecondiTM) is a prodrug of a bifunctional epoxide alkylating agent that converts nonenzymatically under physiological conditions to L-diepoxybutane via the corresponding mono-epoxide intermediate (Figure 5.25). The mono-epoxide intermediate and L-diepoxybutane alkylate DNA at guanine residues, and the formation of DNA interstrand cross-links and guanine-adenine intrastrand cross-links have been reported, followed by DNA fragmentation and apoptosis. Treosulfan is available as a generic throughout most of the world, but in some parts of Europe it is marketed under its original trade name of OvastatTM. Conversion of treosulfan (OvastatTM) into the DNA-reactive L-diepoxybutane via the mono-epoxide intermediate.
Valproate
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
J. Christine Dean, J. Kiffin Penry
Compared to VPA, valpromide offers two minor advantages, but presents one major disadvantage. VPA plasma levels derived from valpromide tend to fluctuate less than those derived from the free acid or sodium salt (95), and valpromide appears to be more effective than VPA in the prevention of febrile seizures (96), however, because it is a potent inhibitor of liver microsomal epoxide hydrolase (at least 100 times as potent as VPA itself) (97), in patients taking CBZ it dramatically increases the levels of CBZ-epoxide (average increase > 300%; range 100 to >800%), causing symptoms such as dizziness and confusion in some patients (98) and possibly increasing the risk of fetal malformations (99). However, interactions associated with valpromide may not be limited just to patients taking CBZ. Inhibition of epoxide hydrolase may have broader implications because the enzyme is important for the detoxification of reactive epoxide metabolites of drugs and environmental pollutants which can be cytotoxic, mutagenic, and carcinogenic (100).
Central Nervous System Effects of Essential Oil Compounds
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Elaine Elisabetsky, Domingos S. Nunes
Curzerene 30 (C15, furan ring), epoxycarvone 31 (C10, epoxide), linalool oxide 32 (C15, cyclic C4-ether), and limonene epoxide 33 (C10, epoxide) are cyclic ethers of different kinds, sizes, and formats. Compounds 30–33 have two or three chiral centers and present four possible optical isomers each, but few conformations to consider.
Anticancer Activity of Leonurus sibiricus L.: Possible Involvement of Intrinsic Apoptotic Pathway
Published in Nutrition and Cancer, 2022
Vasanth Krishnan, Selvakumar Subramaniam, Chang Chia–Chuan, Balamurugan Venkatachalam, Amal Thomas Cheeran, Huang Chi-Ying F.
HPLC analysis of LS-M extracts reveal the presence of carotenoids, including β-carotene and lutein. The majority of carotenoids in the plant photosynthetic tissues is lutein. It is a dihydroxy β, ε carotene accounting for more than 50% of the carotenoids in leaf tissue (43). There are several fruits and vegetables rich in carotenoid content that can prevent several cancers, particularly lung cancer (44). The various isoforms of carotenoids such as zeaxanthin, lutein, and β-carotene reduced the HPV infection as well as cancer cell proliferation (43–50%) (45). Our in vitro studies showed that both lutein or β-carotene has a significant inhibitory effect on HCC. These results correlate with the anticancer activity of LS-M extract on HCC cell lines and indicated the potential involvement of carotenoids in ROS mediated apoptosis. In a previous report, both lutein and lutein epoxide significantly inhibited the cancer growth and induced apoptosis (46). In this study, the mechanism of lutein modulated apoptosis in cancer cell line was attributed to the increased intracellular ROS production and regulation of several apoptotic proteins, including phosphorylation of p53.
Weight of evidence analysis of the tumorigenic potential of 1,3-dichloropropene supports a threshold-based risk assessment
Published in Critical Reviews in Toxicology, 2020
Zhongyu (June) Yan, Michael Bartels, Bhaskar Gollapudi, Jeffrey Driver, Matthew Himmelstein, Sean Gehen, Daland Juberg, Ian van Wesenbeeck, Claire Terry, Reza Rasoulpour
The metabolic fate of 1,3-D via oral exposure has been investigated extensively. 1,3-D is rapidly eliminated from the bloodstream in rodents as evidenced by a prominent initial phase with a half-life of approximately 4–7 min followed by a slower phase with a half-life of 22–43 min. The overall metabolic profile of 1,3-D is very similar for rats and mice based on similar absorption, metabolism, distribution, and elimination in these two species. The routes of excretion for total radio-labeled 1,3-D in rats and mice were via the urine, feces, and as expired CO2. The majority of recovered radiocarbon was found in the urine. 1,3-D is primarily metabolized and detoxified in rats and mice by conjugation with glutathione (GSH) (Figure 2). To a lesser extent, 1,3-D undergoes hydrolysis of the 3-position chlorine to produce acid and alcohol metabolites which are further metabolized to carbon dioxide. Although minor metabolites suggest a trace epoxidation pathway, no detectable epoxide was found in rodents at doses up to 100 mg/kg by gavage administration. Measurable oxidation of 1,3-D to epoxide occurs in the rodent only at extremely high dose levels via a non-relevant exposure route (i.e. ip administration) which resulted in lethality (Schneider 1998; Bartels et al. 2020).
Association between EPHX1 polymorphism rs1051740 and the risk of ovarian cancer: a meta-analysis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
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].