Carcinogens reactive Intermediates

Ghloromethylation. The reactive intermediate, 1-chloromethylnaphthalene [86-52-2] has been produced by the reaction of naphthalene in glacial acetic acid and phosphoric acid with formaldehyde and hydrochloric acid. Heating of these ingredients at 80—85°C at 101.3 kPa (1 atm) with stirring for ca 6 h is required. The potential ha2ard of such chloromethylation reactions, which results from the possible production of small amounts of the powerhil carcinogen methyl chloromethyl ether [107-30-2J, has been reported (21). 

The NO + 03 chemiluminescent reaction [Reactions (1-3)] is utilized in two commercially available GC detectors, the TEA detector, manufactured by Thermal Electric Corporation (Saddle Brook, NJ), and two nitrogen-selective detectors, manufactured by Thermal Electric Corporation and Antek Instruments, respectively. The TEA detector provides a highly sensitive and selective means of analyzing samples for A-nitrosamines, many of which are known carcinogens. These compounds can be found in such diverse matrices as foods, cosmetics, tobacco products, and environmental samples of soil and water. The TEA detector can also be used to quantify nitroaromatics. This class of compounds includes many explosives and various reactive intermediates used in the chemical industry [121]. Several nitroaromatics are known carcinogens, and are found as environmental contaminants. They have been repeatedly identified in organic aerosol particles, formed from the reaction of polycyclic aromatic hydrocarbons with atmospheric nitric acid at the particle surface [122-124], The TEA detector is extremely selective, which aids analyses in complex matrices, but also severely limits the number of potential applications for the detector [125-127],... 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

Marnett LJ. Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as reactive intermediates. Environ Health Perspect 1990 88 5-12. 

Ahokas, J.T., Pelkonen, 0. and K rki, N.T. The possible role of trout liver aryl hydrocarbon hydroxylase in activating aromatic polycyclic carcinogens. In Jollow, D.J. Kocsis, J.J., Snyder, R. and Vainio, H. (Eds.) Biological Reactive Intermediates. Formation, Toxicity, and inactivation (1977) Plenum Press, New York, pp 162-166. 

A snbstantial body of experimental evidence indicates that the formation of a covalent bond between chemical carcinogens and cellnlar macromolecnles represents the first critical step in the multistage process, eventually leading to tumor formation (see Geacintov et al. 1997, references therein). Most chemical carcinogens are not active on their own, but require metabolic activation to produce reactive intermediates capable of binding covalently with target macromolecnles, particularly with deoxyribonucleic acid (DNA), and thereby, initiate cancer. 

Bacteria indigenous to Cr(VI)-polluted areas are Cr(VI) tolerant and/or resistant and have been considered as potential candidates for bioremediation of Cr(VI)-contaminated sites.16 However, the ability of bacteria to reduce Cr(VI) to the less-toxic Cr(III) compounds may produce reactive intermediates (such as Cr(V), Cr(IV), radicals), which are known to be active genotoxins and are likely to be carcinogenic.17 Therefore, the formation and lifetimes of Cr(V) intermediates, produced via bacterial reduction of Cr(VI), need to be evaluated carefully if microorganisms are to be employed as a means for remediation of chromium-polluted subsurface environments. Similarly, Cr(V) accumulation should first be monitored when considering plants and algae as biosorption materials for the bioremediation in the event of chromium pollution.18... 

Earlier progress in these studies has been summarized in reviews published in the last decade, emphasizing carbocations and oxidation dications, RCs, as well as reactive intermediates from the nitro- and nitroso-derivatives. The review article published in 1996 emphasized groundwork studies on protonation as well as oxidation (both RCs and stable dications) of polycyclic arenes and explored possible relationships between charge distribution and carcinogenicity, in concert with its... 

Two chapters in this volume describe the generation of carbocations and the characterization of their structure and reactivity in strikingly different milieu. The study of the reactions in water of persistent carbocations generated from aromatic and heteroaromatic compounds has long provided useful models for the reactions of DNA with reactive electrophiles. The chapter by Laali and Borosky on the formation of stable carbocations and onium ions in water describes correlations between structure-reactivity relationships, obtained from wholly chemical studies on these carbocations, and the carcinogenic potency of these carbocations. The landmark studies to characterize reactive carbocations under stable superacidic conditions led to the award of the 1994 Nobel Prize in Chemistry to George Olah. The chapter by Reddy and Prakash describes the creative extension of this earlier work to the study of extremely unstable carbodications under conditions where they show long lifetimes. The chapter provides a lucid description of modern experimental methods to characterize these unusual reactive intermediates and of ab initio calculations to model the results of experimental work. 

It is not known how chemicals cause cancer. A fascinating aspect of the story is that many "carcinogenic" chemicals are in fact, not the culprits responsible for cancer induction. The metabolic processes of the body change the chemicals from relatively innocuous substances into reactive intermediates which in as yet unknown fashion, trigger the chain of events which finally result in tumor formation. In other words, chemical carcinogenesis is an effect of "failed" detoxification. 

Reactive chemicals or their reactive intermediates, such as free radicals and other electrophilic species, may form essentially irreversible covalent bonds with adjacent macromolecules, such as proteins, lipids, and DNA, resulting in the formation of adducts. Covalent adducts can disrupt the normal function of such macromolecules and result in a broad spectrum of toxic responses. These may range from localized transient skin irritation to systemic target organ toxicity (such as hepatotoxicity, neurotoxicity, and renal toxicity), genotoxicity, or carcinogenicity. 

Most chemical carcinogens are not active on their own, but require metabolic activation to produce reactive intermediates capable of binding covalently to target macromolecules, in particular DNA, and thereby initiate cancer. 

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