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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
A substituted benzoquinone ring has been employed as an “anchor” for aziridine rings in the experimental agents AZQ and BZQ. The aziridine moieties are deactivated by the withdrawal of electrons from their nitrogens into the quinone carbonyl groups via the six-membered ring. These molecules have been employed as experimental bioreductive prodrugs because reduction of the quinone ring to either the semiquinone or the hydroxyquinone species reverses the electron flow, thus increasing the basicity of the aziridine nitrogens which allows them to become activated via protonation. No benzoquinone agents of this type have yet been approved for clinical use.
Benzene Metabolism (Toxicokinetics and the Molecular Aspects of Benzene Toxicity)
Published in Muzaffer Aksoy, Benzene Carcinogenicity, 2017
Keith R. Cooper, Robert Snyder
Erexson et al.154 exposed human peripheral blood lymphocytes to benzene, phenol, catechol, 1,2,4-benzenetriol, hydroquinone, and benzoquinone and showed a dose-dependent increase in SCE, decreases in mitotic indices, and inhibition of cell cycle kinetics.
Comparison between patch test results of natural dyes and standard allergens in batik workers with occupational contact dermatitis
Published in Cutaneous and Ocular Toxicology, 2022
Eka Devinta Novi Diana, Suci Widhiati, Moerbono Mochtar, Muhammad Eko Irawanto
Some standard allergen properties are thought to cause ACD, including having a small molecular weight (less than 500 Da), being electrophilic, and being a strong sensitiser. The study of Handa et al. in India reported that a positive patch test for PPD of 0.1% was found in 13% of cases18. In this study, out of 5 subjects with ACD due to exposure to standard allergens, a positive patch test for 0.1% PPD was found in 1 subject (20%). P-phenylenediamine is a hapten with a small molecular weight of 108.1 Da. The low molecular weight of PPD facilitates the penetration of allergens into the stratum corneum, which in turn causes sensitisation. P-phenylenediamine easily binds to proteins to form a complete antigen and is electrophilic. P-phenylenediamine sensitisation of the skin is thought to be due to the formation of benzoquinone. P-phenylenediamine, which is exposed to oxygen (O2) in the air for a long time, will be oxidised to reactive benzoquinone diimine, a necessary substance to react with proteins19.
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
Even though the data of Calder and coworkers implicated NAPQI as a reactive metabolite, they were unable to purify it and thus identified it by an indirect technique, as a Diels–Alder adduct. Since they were unable purify it they were not able to perform detailed studies on its chemical properties (Calder et al. 1973). Nelson and coworkers were able to synthesize pure NAPQI by oxidation of APAP with silver oxide (AgO) in chloroform and study its chemical reactivity (Dahlin and Nelson 1982). The compound was unstable in aqueous buffer with a half-life of approximately 11 minutes. It decomposed to a number of products including hydrolysis to benzoquinone. In isolated liver cells, it was about 10 times more toxic than APAP and was also toxic in vivo (Dahlin and Nelson 1982). Subsequently, using purified cytochromes P450, radiolabeled APAP and cumene hydroxide HPLC analysis indicated a radiolabeled metabolite with the retention time of NAPQI. In the presence of NADPH and NADPH-cytochrome P450 reductase, steady-state levels of NAPQI were below their detection limits of 6.7 × 10–8 M. Thus, they were forced to use cumene hydroperoxide in the incubation mixture. In the presence of GSH, an APAP–GSH conjugate was formed (Dahlin et al. 1984). Overall, these data support the hypothesis that NAPQI is the major reactive metabolite of APAP (Figure 3).
Genomics of Detoxification: How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies Including Nutrition for Environmentally Acquired Illness
Published in Journal of the American College of Nutrition, 2020
Sharon R. Hausman-Cohen, Lee J. Hausman-Cohen, Grant E. Williams, Carol E. Bilich
While there are many different genes associated with risk of benzene toxicity including CYP2E1 which will be discussed later, but for the purpose of clarity, this article will focus here just on the highly significant NAD(P)H quinone oxidoreductase 1 (NQO1). The NQO1 gene encodes a reductase known to be important for its ability to convert inactive forms of Vitamin E and CoQ10 to their active forms, which are themselves important antioxidants (37). However, within the context of benzene, NQO1 most notably is involved in the reduction of benzoquinones into hydroquinones (Figure 3) (38). Both benzoquinone and hydroquinone are natural stages within the metabolism of benzene and have been associated with toxicity. However, partial or total loss of NQO1 function (and thus greater concentration of benzoquinone) results in more severe benzene toxicity, implicating a lessened toxicity when in a reduced state (hydroquinone). Indeed, this has been confirmed by research, demonstrating the importance of NQO1 to relief of benzene toxicity (39). For those interested, this is hypothesized to be due to hydroquinone’s mechanism of toxicity to be indirect via creation of ROS (and thus addressable by alternate pathways), while benzoquinones directly damage biological molecules such as DNA, and are difficult to attenuate through alternate mechanisms (38, 40).