METABOLIC ACTIVATION OF CHEMICAL CARCINOGENS AND DNA ADDUCT FORMATION in .NET framework

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METABOLIC ACTIVATION OF CHEMICAL CARCINOGENS AND DNA ADDUCT FORMATION
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Table 12.6 Some General Mechanisms of Tumor Promotion Selective proliferation of initiated cells Increased responsiveness to and/or production of growth factors, hormones, and other active molecules Decreased responsiveness to inhibitory growth signals Perturbation of intracellular signaling pathways Altered differentiation Inhibition of terminal differentiation of initiated cells Acceleration of differentiation of uninitiated cells Inhibition of apoptosis in initiated cells Toxicity/compensatory hyperplasia Resistance to toxicity by initiated cells
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12.6 METABOLIC ACTIVATION OF CHEMICAL CARCINOGENS AND DNA ADDUCT FORMATION
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Having described the general aspects of chemical carcinogenesis including the initiation-promotion model, we now examine some aspects of chemical carcinogenesis in more detail. Metabolic activation of chemical carcinogens by cytochromes P450 is well documented. The metabolism of benzo[a]pyrene has been extensively studied and at least 15 major phase I metabolites have been identi ed. Many of these metabolites are further metabolized by phase II enzymes to produce numerous different metabolites. Extensive research has elucidated which of these metabolites and pathways are important in the carcinogenic process. As shown in Figure 12.12, benzo[a]pyrene is metabolized by cytochrome P450 to benzo[a]pyrene-7,8 epoxide, which is then hydrated by epoxide hydrolase to form benzo[a]pyrene-7,8-diol. Benzo[a]pyrene-7,8-diol is considered the proximate carcinogen since it must be further metabolized by cytochrome P450 to form the ultimate carcinogen, the bay region diol epoxide, (+)-benzo[a]pyrene7,8-diol-9,10-epoxide-2. It is this reactive intermediate that binds covalently to DNA, forming DNA adducts. (+)-Benzo[a]pyrene-7,8-diol-9,10-epoxide-2 binds preferentially to deoxyguanine residues, forming N -2 adduct. (+)-Benzo[a]pyrene-7,8-diol9,10-epoxide-2 is highly mutagenic in eukaryotic and prokaryotic cells and carcinogenic in rodents. It is important to note that not only is the chemical con guration of the metabolites of many polycyclic aromatic hydrocarbons important for their carcinogenic activity, but so is their chemical conformation/stereospeci city (Figure 12.12). For example, four different stereoisomers of benzo[a]pyrene-7,8-diol-9,10 epoxide are formed. Each one only differs with respect to whether the epoxide or hydroxyl groups are above or below the plane of the at benzo[a]pyrene molecule, but only one, (+)benzo[a]pyrene-7,8-diol-9,10-epoxide-2, has signi cant carcinogenic potential. Many polycyclic aromatic hydrocarbons are metabolized to bay-region diol epoxides. The bay-region theory suggests that the bay-region diol epoxides are the ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. DNA can be altered by strand breakage, oxidative damage, large bulky adducts, and alkylation. Carcinogens such as N-methyl-N -nitro-N-nitrosoguanidine and methyl
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OH (+)-BP 7,8-diol-9, 10-epoxide-2 HO
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O OH (+)-BP 7,8-oxide ( )-BP 7,8-dihydrodiol
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HO OH (+)-BP 7,8-diol-9, 10-epoxide-1 HO OH ( )-BP 7,8-oxide (+)-BP 7,8-dihydrodiol HO OH ( )-BP 7,8-diol-9, 10-epoxide-2
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Figure 12.12 Benzo[a]pyrene metabolism to the ultimate carcinogenic species. Heavy arrows indicate major metabolic pathways, * represents ultimate carcinogenic species. (Adapted from A. H. Conney, Cancer Res. 42: 4875, 1982.)
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methanesulfonate alkylate DNA to produce N-alkylated and O-alkylated purines and pyrimidines. Ionizing radiation and reactive oxygen species commonly oxidize guanine to produce 8-oxoguanine. Formation of DNA adducts may involve any of the bases, although the N -7 position of guanine is one the most nucleophilic sites in DNA. Of importance is how long the adduct is retained in the DNA. (+)-Benzo[a]pyrene-7,8diol-9,10-epoxide-2 forms adducts mainly at guanine N -2, while a atoxin B1 epoxide, another well-studied rodent and human carcinogen, binds preferentially to the N -7 position of guanine. For some carcinogens there is a strong correlation between the formation of very speci c DNA-adducts and tumorigenicity. Quantitation and identi cation of speci c carcinogen adducts may be useful as biomarkers of exposure. Importantly, the identi cation of speci c DNA-adducts has allowed for the prediction of speci c point mutations that would likely occur in the daughter cell provided that there was no repair of the DNA-adduct in the parent cell. As will be discussed in a later section, some of these expected mutations have been identi ed in speci c oncogenes and tumor suppressor genes in chemically induced rodent tumors, providing support that the covalent carcinogen binding produced the observed mutation. In several cases, speci c base pair changes in p53 tumor suppressor gene in human tumors are associated with a mutational spectrum that is consistent with exposure of the individual to a speci c carcinogen. For example, the mutation spectra identi ed in p53 in human tumors thought to result from the exposure of the individual to ultraviolet radiation (UVR), a atoxin, and benzo[a]pyrene (from cigarette smoke), are consistent with the observed speci c mutational damage in p53 induced by these agents in experimental cellular systems.
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