Carcinogen metabolic activation requirements

In recent years, it has become evident that for many well-studied chemical carcinogens, metabolic activation to a reactive intermediate in the host is required in order for reaction with DNA and other cellular macromolecules to occur (31, 32). Thus, many carcinogens appear to be precarcinogens, which are metabolized vivo to their reactive forms, or ultimate... 

Alternative pathways of activation of nitrosamines, including 3-hydroxylation followed by sulfate conjugation and the formation of alkoxydiazen-ium ions are discussed. The formation of alkyldiazo-nium ions from trialkyltriazenes is presented to show that the formation of the putative ultimate carcinogens from nitrosamines can be studied in a system not requiring metabolic activation,... 

These nltrosated amides, In contrast to the nltrosamlnes, do not require metabolic activation in order to alkylate cellular nucleophilic targets. Thus, many of these substances are directly acting mutagens and also carcinogens (38. ... 

Covalent binding of chemical carcinogens to cellular macromolecules, DNA, RNA and protein, is wel1-accepted to be the first step in the tumor initiation process ( 1, 2). Most carcinogens, including polycyclic aromatic hydrocarbons (PAH), require metabolic activation to produce the ultimate electrophilic species which react with cellular macromolecules. Understanding the mechanisms of activation and the enzymes which catalyze them is critical to elucidating the tumor initiation process. 

Oxidation is intimately linked to the activation of polycyclic aromatic hydrocarbons (PAH) to carcinogens (1-3). Oxidation of PAH in animals and man is enzyme-catalyzed and is a response to the introduction of foreign compounds into the cellular environment. The most intensively studied enzyme of PAH oxidation is cytochrome P-450, which is a mixed-function oxidase that receives its electrons from NADPH via a one or two component electron transport chain (10. Some forms of this enzyme play a major role in systemic metabolism of PAH (4 ). However, there are numerous examples of carcinogens that require metabolic activation, including PAH, that induce cancer in tissues with low mixed-function oxidase activity ( 5). In order to comprehensively evaluate the metabolic activation of PAH, one must consider all cellular pathways for their oxidative activation. 

This compound requires metabolic activation by liver microsomes to yield highly mutagenic derivatives in the Ames test204. In addition, IQ is a multipotent animal carcinogen that is metabolized by prostaglandin-H synthase205 and the hepatic cytochrome P-450 system204. 

Cytochrome P-U50 in carcinogen metabolism. In spite of the bewildering number of carcinogens involved the important and unifying fact is, that most of the organic carcinogens are not carcinogenic per se, but require metabolic activation in situ by cytochrome P-i 50 mediated aryl hydrocarbon hydroxylase (AHH, also known as BP hydroxylase (EC 1.lU.lit.2)). 

AFB has been shown to require metabolic activation to its ultimate carcinogenic species (18, 19, 20, 21, 22) which is believed to be a 2,3-epoxide form of AFB (OAFB) (19, 23-29). 

Some examples will be seen in later sections of carcinogens that seem not to require metabolic activation to electrophiles, and which do not possess significant electrophilic properties themselves these agents appear not to be involved in the initial DNA-damaging event, but rather at later stages of the neoplastic process. 

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. 

Before administration of a NME to man, a mutagenicity test in bacterial cells (Ames test), with and without metabolic activation, and tests for chromosomal aberrations in mammalian cells should be negative. Any positive or equivocal results will require additional tests to be performed before proceeding to man. Studies of embryo-foetal toxicity should be performed before administration of a NME to women of reproductive potential. Studies of fertility, early embryonic development and pre- and post-natal development are not required at this stage of development neither are carcinogenicity studies. 

As discussed in detail in Section 5, with chemical carcinogens, the route of exposure can be an important determinant of the site of cancer induction, particularly with direct-acting carcinogens which may act at the initial point of contact. For the majority of carcinogens, however, which require metabolic activation, the location in the body of activating enzymes is thought to be the major determinant of the site of carcinogenesis. 

Stetka, D.G. and Wolff, S. (1976a). Sister chromatid exchange as an assay for genetic damage induced by mutagen-carcinogens. I. In vivo test for compounds requiring metabolic activation, Mutat. Res. 41,333. 

The carcinogenicity of af la toxin is reduced by protein deficiency, presumably because of reduced metabolic activation to the epoxide intermediate, which may be the ultimate carcinogen, which binds to DNA (Fig. 5.14). A deficiency in dietary fatty acids also decreases the activity of the microsomal enzymes. Thus, ethylmorphine, hexobarbital, and aniline metabolism are decreased, possibly because lipid is required for cytochromes P-450. Thus, a deficiency of essential fatty acids leads to a decline in both cytochromes P-450 levels and activity in vivo. 

BULL Okay, certain compounds require metabolic activation to electrophilic intermediates, and the others are electrophiles themselves. Both types of compounds can be carcinogenic. Presumably, the latter group [electrophiles] would be the ones that would be destroyed by the concentrating methods. The worry would be that nucleophilic material in the concentrate could react with the electrophiles and destroy them as you concentrate the samples. This would be proportional to the amount of compounds present and the degree and method of concentration. Ultimately, you can expect them to disappear. 

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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