Benzene Metabolism (Toxicokinetics and the Molecular Aspects of Benzene Toxicity)
Muzaffer Aksoy in Benzene Carcinogenicity, 2017
Benzene was also shown to inhibit mitochondrial translation, which may be due to a lack of messenger RNA and a subsequent disaggregation of polysomes. Both hydroquinone and its oxidative product, p-benzoquinone, inhibited DNA replication in rat liver and bone marrow mitochondria (MT) in a dose-dependent manner.126 p-Benzoquinone, hydroquinone, and 1,2,4-benzenetriol inhibited the activity of partially purified MTDNA polymerase gamma. The interaction of the chemicals was with the -SH group on the enzyme and not the template.127
Interaction of L-ascorbic acid and α-tocopherol in alleviating 1, 4-benzoquinone, a metabolite of benzene induced genotoxicity in male Wistar rats
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Ritu Mishra, Karabi Dutta, Manuj Kr. Bharali
Metabolic activation of benzene is necessary to exert its toxic effect and it is mediated through the formation of many intermediates which include phenol, hydroquinone, muconaldehyde and catechol [1]. Bio-activation of benzene takes place primarily in the liver by cytochrome p450 mediated pathway and phenolic compounds (hydroquinone) so formed in the liver are converted to 1,4-benzoquinone (BQ) in the bone marrow through myeloperoxidase mediated pathway [2]. BQ is the most reactive of all the metabolites of benzene that causes severe genotoxicity in the hematopoietic system leading to leukemia and lymphoma [3]. BQ is known to exert its genotoxic effect by inhibiting the activity of topoisomerase II which leads to severe DNA strand breaks and other genotoxic events, thus converting the essential cellular enzyme into a toxin [4]. Further BQ has been reported to cause bone marrow toxicity and hematotoxicity via oxidative stress and further damage to genetic material. The oxidative DNA damage potential of BQ has also been attributed to the formation of reactive oxygen species (ROS) and covalent binding in benzene-induced toxicity [5].
Human biomonitoring of low-level benzene exposures
Published in Critical Reviews in Toxicology, 2022
Peter J. Boogaard
Apart for measuring benzene itself, blood has also been investigated as specimen for the analysis of protein adducts of benzene metabolites. Benzene undergoes oxidative metabolism to several electrophilic metabolites that can bind to blood proteins such as albumin and haemoglobin. The primary oxidative metabolite is benzene oxide, which is highly reactive and can bind to cysteine sulfhydryl residues and to N-terminal valine residues in proteins. S-Phenylcysteine could indeed be detected in both the haemoglobin and albumin of exposed individuals (Bechtold et al. 1992; Bechtold et al. 1992; Yeowell-O'Connell et al. 1996; Yeowell-O'Connell et al. 1998; Hanway et al. 2000). Benzene oxide is unstable and will re-arrange quickly to phenol that can be oxidised to 1,2- and 1,4-benzoquinone which can also bind to the cysteine residues in both haemoglobin and albumin in humans (Yeowell-O'Connell et al. 2001; Rappaport et al. 2002; Rappaport et al. 2005). It turned out, however, that the adduct levels did not correlate well with airborne exposure levels (Yeowell-O'Connell et al. 2001, Lin et al. 2006, Lin et al. 2007). This may be due to the instability of the adducts and is most likely also influenced by the relatively high backgrounds in humans of phenol and hydroquinones from the diet (McDonald et al. 2001; Johnson et al. 2007).
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).
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