Formation of DNA adducts

The pollutant (xenobiotic) forms a stable covalent bond with its target. Examples include the phosphorylation of cholinesterases by the oxon forms of OPs, the formation of DNA adducts by the reactive epoxides of benzo[a] pyrene and other PAHs, and the binding of organomercury compounds to... 

Compared to the extensive data that have been obtained on the mutagenicity of nitro PAHs in S. typhimurium, relatively little is known about the metabolism of these compounds in this organism. Messier et al. (67) reported that incubation of 1-nitropyrene with S. typhimurium TA98 yielded 1-aminopyrene and 1-acetylaminopyrene as major and minor metabolites, respectively. The reduction of 1-nitropyrene was slow and was accompanied by a slow formation of DNA adducts. When incubations were conducted with the nitroreductase-deficient strain, TA100 F50, both the extent of 1-amino-pyrene formation and DNA binding decreased. Howard ej al. (71,115) also found reduction of 1-nitropyrene to 1-aminopyrene in strains TA98, TA1538 and ATCC 14028. 

Faisal, M., Formation of DNA adducts in hemopoietic organs and isolated leukocytes of the mummichog, Fundulus heteroclitus, following exposure to benzo-a-pyrene, Mar. Environ. Res., 46, 359, 1998. 

The formation of BaP 9,10-epoxide is considered a reaction of detoxification of BaP, as is the formation of its K-region epoxide. However, this last statement must now be qualified by the recent finding that the K-region dihydrodiol of benzo[a]pyrene, i.e., /ra .v-4,5-dihydro-4,5-dihydroxy-BaP (10.35, Fig. 10.13), can ultimately form DNA adducts. This is due to its further metabolism to bis [dihydrodiols] such as 1,2,4,5-, 4,5,7,8-, and 4,5,9,10-bis[dihydrodiol]. The tran,y-/ra ,y-BaP-4,5,7,8-bis[dihydrodiol] has been shown to be a metabolic intermediate in the formation of DNA-adducts [103],... 

Carmichael P, Pfau W, Ni She M, et al. 1991. Formation of DNA-adducts in human and mouse skin following treatment with used engine oil and elucidation of some of the contributing PAHs by 32P-poslabeling (meeting abstract). Proc Annu Meet Am Assoc Cancer Res 32 A582. 

Hydrazine induces gene mutations in bacteria, yeast and Drosophila, and in vivo treatment of rodents results in the formation of DNA adducts. ... 

Chronic exposure to hepatotoxic doses of DMN has also been found to suppress humoral and cellular immunity in mice. DMN is geno-toxic in a wide variety of assays inducing DNA synthesis, chromosomal aberrations, sister chromatid exchange, and bacterial mutations. " The formation of DNA adducts by metabolites of DMN may play a critical role in the carcinogenic process."... 

Acrylonitrile is mutagenic, especially after bioactivation by a microsomal system. Since formation of DNA adducts with acrylonitrile in vitro is strongly increased by formation of its epoxide, it is very likely that the genotoxicity of acrylonitrile is mediated primarily by this metabolite. The epoxide, therefore, may be implicated in the carcinogenicity of acrylonitrile. 

Levay, G. Bodell. W.J. (1996) Role of hydrogen peroxide in the formation of DNA adducts in HL-60 cells treated with benzene metabolites. Biochem. biophys. Res. Comm., 222, 44-49... 

Gansewendt, B., Foest, U., Xu, D., Hallier, E., Bolt, H.M. Peter. H. (1991) Formation of DNA adducts in F-344 rats after oral administration or inhalation of [ C]methyl bromide. Food chem. Toxicol., 29, 557-563... 

Tetrachlorohydroquinone is more toxic to rats and human liver cells than its parent, pentachlorophenol.17 Lipid peroxidation and liver damage in rats are consistent with free radical mechanisms of adverse biochemical effects from tetrachlorohydroquinone and pentachlorophenol. Liver cells exposed to tetrachlorohydroquinone and tetrachloro-l,4-benzoquinone have shown the formation of DNA adducts.18... 

In addition to studies dealing with structural chromosomal changes, effects on DNA were also investigated. Oral exposure to 1 g/kg/week of 2,3,7,8-TCDD or 1,2,3,7,8-PCDD for up to 6 months did not increase the formation of DNA adducts in Sprague-Dawley rats (Randerath et al. 1989). A single oral dose of 2,3,7,8-TCDD (25-100 g/kg) caused time-dependent increases in the induction of DNA single-strand breaks (and lipid peroxidation) in hepatic cells of Sprague-Dawley rats terminated within 3-14 days after the treatment (Wahba et al. 1989). 

Exposure of cells to carcinogens may result in the formation of DNA adducts varying in size from methyl groups to bulky structures, such as metabolites of polycyclic aromatic hydrocarbons and aromatic amines. In vivo, these adducts usually are removed enzymatically and at different rates from the DNA. Because the liver is the main site of activation of chemical carcinogens, the DNA of this organ usually forms more adducts. Direct detection and measurement of DNA damage are thus possible, in principle, by detection and measurement of the bound adduct. Because the number of adducts is usually extremely small, very sensitive methods cure required for their measurement. 

Essential oil from nutmeg suppressed the formation of DNA adducts by afla-toxin B1 in vitro in a microsomal enzyme-mediated reaction (Hashim et al., 1994). A diet containing 1% mace inhibited the DMBA-induced papillomagenesis in the skin of male Swiss albino mice (Jannu et al., 1991). 

Hashim, S., Aboobaker, V.S, Madhubala, R., Bhattacharya, R.K. and Rao, A.R. (1994) Modulatory effects of essential oils from spices on the formation of DNA adduct by aflatoxin B1 in vitro. Nutrition and Cancer 21,169-175. 

During the past few years, the general sequence of events in the formation of DNA adducts with polynuclear aromatic hydrocarbons (PAH) and its possible relationship to neoplasia has been determined (1.2). Of particular importance are the biotransformations that convert PAH first to hydroxylated primary metabolites, which are then conjugated to from secondary metabolites and excreted by the organism. In the metabolic processes associated with the formation of the primary metabolites highly reactive intermediates are formed which may bind to cell macromolecules including DNA fl-3). 

BaP is an acknowledged lung carcinogen. Exposure of mice to it results in the formation of DNA adducts in the lung. When BaP was co-adminis-tered with pentachlorophenol (PCP), the PCP potentiated the effect of BaP and a significant increase in the number of DNA adducts was observed. M This effect, however, was observed only in adult mice and not in infant mice. The authors of the study conclude that different mechanisms are involved in the metabolism of BaP for adult versus infant mice. 

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