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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Bromobenzene is both hepatotoxic and nephrotoxic to rats. The primary metabolite in liver that is responsible for covalent binding and toxicity is p-bromophenol. In kidney, however, the initial species responsible for proximal tubular necrosis is 0-bromophenol, which is produced by hepatic cytochrome P-450 and it, or a metabolite, is then translocated to the kidneys for further metabolism (Lau et al., 1984a). The actual species translocated from liver to kidneys was subsequently identified as 2-bromohydroquinone (Lau et al., 1984b). The bioactivation pathway responsible for bromobenzene nephrotoxicity (Figure 9) is an example of a situation where the liver converts the parent chemical to a stable metabolite (P → M2; Figure 1) that is translocated to the kidney and is converted to a reactive metabolite (M2 → Ml; Figure 1) that ultimately produces the toxicity.
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
APAP epoxidation had been suggested by a number of investigators as another possible toxic mechanism. Epoxidation was known to be important in the carcinogenicity of polycyclic aromatic hydrocarbons (Nebert et al. 1976) and the hepatotoxicity of bromobenzene (Jollow et al. 1974). Thus, the potential 3,4-epoxidation of APAP was evaluated. By this mechanism, the 3,4-epoxide could react directly with a nucleophile, or the ring could open to yield the hydrated NAPQI and dehydration would yield NAPQI. This mechanism was investigated by incubating APAP in a microsomal incubation mixture in the presence of GSH and an 18O2 atmosphere. If 3,4-epoxidation were the mechanism of metabolic activation of APAP to yield a GSH conjugate, then 18O would be incorporated into the APAP–GS metabolite at a 50% level. Isolation of the APAP–GS metabolite from this experiment and analysis by mass spectrometry indicated no incorporation of 18O (Hinson et al. 1977). Also, the p-18O-APAP was synthesized and incubated with GSH in a microsomal incubation mixture and 18O was not lost in the isolated 18O-APAP-GS metabolite. Finally, p-18O-APAP was administered to hamsters and the urinary APAP mercapturate (NAC-APAP) metabolite isolated (Hinson, Nelson, et al. 1979). The 18O content in the mercapturate was the same as that in the administered p-18O-APAP. Thus, 3,4-epoxidation was not the mechanism of metabolic activation of APAP to a reactive metabolite (Figure 3(B)).
The metabolic fate and effects of 2-Bromophenol in male Sprague–Dawley rats
Published in Xenobiotica, 2019
Kyrillos N. Adesina-Georgiadis, Nicola Gray, Robert S. Plumb, David F. Thompson, Elaine Holmes, Jeremy K. Nicholson, Ian D. Wilson
The compound 2-bromophenol is a metabolite of bromobenzene, a well-known nephro- and hepatotoxin, which has been used as a solvent, fire retardant, and a component of motor oils. Following ingestion, bromobenzene is metabolised in the liver to a range of oxidised metabolites including 2-bromophenol and 2-bromohydroxyquinone (Lau et al., 1984a). Both 2-bromophenol and 2-bromohydroxyquinone are readily transported from the liver to the kidneys and the reaction of the latter with glutathione produces various mono-and di-substituted conjugates (Parke and Piotrowski, 1996). The accumulation of these conjugates, in addition to the depletion of the local glutathione pool, is thought to be the cause of renal toxicity (Lau et al., 1984b). In addition to 2-bromohydroxyquinone, it has been shown following i.p. administration (at doses from 1.28 mmol/kg upwards), that 2-bromophenol is also a nephrotoxin in the rat (Lau et al., 1984b). In a subsequent study, Bruchajzer et al. (2002) observed changes in the composition of the urine and changes in glutathione concentrations in the kidney of rats, which were administered the compound, including increased protein excretion and elevated epithelial cell content, which they considered as being due to kidney damage. However, they also observed variability in the concentrations of “classic markers of nephrotoxicity” such as creatinine.
Discovery of indole-3-butyric acid derivatives as potent histone deacetylase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Yiming Chen, Lihui Zhang, Lin Zhang, Qixiao Jiang, Lei Zhang
Based on lead structure IBHA, a series of indol-3-ylbutyric acid derivatives were synthesised according to the procedures described in Scheme 1. The starting material IBA was coupled with a series of bromobenzene. The other material, 4-aminobenzoic acid, was protected by a methyl ester. The intermediates I1b–I13b were derived by conjugation of b and I1a–I13a. Target molecules I1–I17 were synthesised by treatment of corresponding intermediates (I1b–I13b) with NH2OK in methanol. The hydrazide compounds were generated by hydrazinolysis, condensation, and reduction reactions.