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Biotransformation of Occupational Carcinogens
Published in Stephen K. Hall, Joana Chakraborty, Randall J. Ruch, Chemical Exposure and Toxic Responses, 2020
The metabolism of 2-acetylaminofluorene (AAF) is outlined in Figure 17.9. AAF can undergo both ring and N-hydroxylation in a number of species, including the human, but the N-hydroxylation step is of unique importance in the activation of AAF to its ultimate carcinogenic form. The ring hydroxylations are considered detoxification reactions. N-hydroxy-AAF is a substrate for conjugation reactions, and its O-glucuronide is quantitatively the most abundant form in most species, with lesser amounts of the O-glucuronide of N-hydroxy-2-aminofluorene being produced. Sulfation of N-hydroxy-AAF has been related to susceptibility of rats to AAF-induced heptocarcinogenesis. The sulfate ester of N-hydroxy-AAF is a highly unstable compound which reacts rapidly with nucleic acids and proteins at neutral pH. Hence, there is only indirect evidence that this conjugate is a proximate carcinogenic form of AAF. N-hydroxy-AAF is readily deacetylated by microsomal esterases to yield the hydroxylamine, N-hydroxy-2-aminofluorene. The acetyl group of N-hydroxy-AAF can also be transferred to the hydroxyl moiety, a reaction catalyzed by a soluble N-O-acetyltransferase. A variety of studies have shown that deacetylation or N-O-transacetylation are probably more important than sulfation in the activation of N-hydroxy-AAF to its ultimate carcinogenic form. Whether N-hydroxy-AAF interacts with nucleic acid through the formation of an arylnitrenium ion, or through one-electron oxidation yielding nitroxyl free radicals which dismutate to give 2-nitrosofluorene and N-acetoxy-AAF is not clear. The bulk of the evidence favors the nitrenium ion pathway.
N-Heterocycles
Published in Navjeet Kaur, Metals and Non-Metals, 2020
N-Methoxy-3-(4-halophenyl)propanamides have a tendency to form spirodienones having 1-azaspiro[4.5] decane ring system via intramolecular ipso-cyclization of nitrenium ion generated with HTIB in trifluoroethanol (Scheme 34) [116]. 2,1-Benzothiazine derivatives are also synthesized from sulfonamides [117] and (–)-lapatin B via oxidative cyclization of N,N-diacetylglyantrypine by HTIB-promoted cyclization of appropriate amides [90, 118].
Lupus erythematosus syndrome induced by drugs
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Lupus-inducing drugs are generally not cytotoxic at therapeutically relevant concentrations, a property which would have precluded their medicinal use, although activated lymphocytes were reported to be killed by chlorpromazine.41 However, cytopenias associated with certain drugs may be related to the capacity of various reactive drug metabolites to directly cause cell death in in-vitro studies. This would be a non-immune-mediated process. Demonstration that procainamide–hydroxylamine (PAHA), the oxidative metabolite of procainamide (see Fig. 27.1), can under certain in-vitro conditions directly kill a wide variety of cells at pharmacologically relevant concentrations,23,50–52 or enhance reactive oxygen species generation by murine macrophage53 and human neutrophils,52 is consistent with this view. Apoptosis rather than necrotic cell death was mediated by sulfamethoxazole–hydroxylamine54 or by the nitrenium ion of clozapine.55 Cell death may be initiated by damage to the plasma or mitochondrial membrane or by covalent binding to critical intracellular molecules or may be due to redox cycling with oxidized and reduced forms of nicotinamide adenine dinucleotide, depleting the cell of its energy stores as suggested by the correlation between cell reducing potential and sensitivity to PAHA cytotoxicity.50 Cytotoxic drug metabolites generated by neutrophils in vitro have been demonstrated for amodiaquine, carbamazepine, chlorpromazine, clozapine, hydralazine, isoniazid, procainamide, pro-pylthiouracil, quinidine and sulfonamides at therapeutically feasible concentrations. Cytopenia could occur by killing of stem cells if reactive drug metabolites were produced by myeloperoxidase released from immature promyelocytes undergoing granulopoiesis or from activated neutrophils recirculating into the bone marrow. In addition, certain haematopoietic cell lineages sensitized by an immune-mediated mechanism because of drug binding to the cell surface could be destroyed by an otherwise subtoxic concentration of a reactive drug metabolite. Lymphocytes from patients with a history of agranulocytosis secondary to clozapine therapy were somewhat more sensitive to the cytotoxic effects of oxidative metabolites of clozapine than normals or patients who did not develop agranulocytosis,56,57 possibly related to differences in drug bioinactivation by intracellular glutathione or cysteine.58 However, while it is possible that direct cytotoxicity of drug metabolites could be an independent pathogenic mechanism especially in certain susceptible populations, such a process cannot explain the bulk of the immune abnormalities in DIL.
Overview of biological mechanisms of human carcinogens
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Nicholas Birkett, Mustafa Al-Zoughool, Michael Bird, Robert A. Baan, Jan Zielinski, Daniel Krewski
4-Aminobiphenyl is a member of the aromatic amine family. that shares carcinogenic mechanisms with other members of this family (see overview, above). The genotoxic effects of aromatic amines (including 4-aminobiphenyl) are ‘well established on the basis of mutagenicity and clastogenicity observed in numerous in vitro and in vivo assays that show the capability of these compounds to form DNA adducts after metabolic activation to electrophilic intermediates’ (IARC 2012f, 48). Micronuclei were observed in several studies. 4-Aminobiphenyl is activated through N-hydroxylation in the liver. The resulting metabolite is highly electrophilic and forms DNA adducts. The N-hydroxy metabolite is glucuronidated and excreted through the kidney. However, in the acidic environment in the bladder lumen the N-hydroxy metabolite is formed again. NAT1-mediated O-acetylation may then occur, which leads to the production of the highly reactive aryl nitrenium ion, and formation of DNA adducts. Mutations were induced when 4-aminobiphenyl was tested on S. typhimurium in the presence of S9-mediated metabolic activation. 4-Aminobiphenyl induced mutations at the HPRT locus and chromosomal instability in human bladder epithelial cells. 4-Aminobiphenyl-mediated mutations were found in h-Ras (mouse) and TP53 (human bladder cells).