Chemical metabolic activation requirements

Nitrosamines require metabolic activation in order to produce a chemical species that will alkylate nucleophilic sites on a biomolecule such as DNA (1, . The crucial initial step in the... 

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. 

If the neurotoxicity of /7-hexane was potentiated in this study by co-exposure to acetone, the level of n-hexane alone required to produce these effects would be higher than 58 ppm and the MRL level would be higher. Results from simulations with a PBPK model that accurately predicted /7-hexane blood and 2,5-hexanedione urine levels (Perbellini et al. 1986, 1990a) indicate that at concentrations of 50 ppm, the rate-limiting factor in /7-hexane metabolism is delivery to the liver, not metabolic activity. This suggests that at this concentration (and at the MRL concentration of 0.6 ppm), induction of P-450 enzymes in the liver by acetone or other chemicals would not affect the rate at which 2,5-hexanedione was produced. 

A known clastogen should always be included as a positive control. When metabolic activation is used, a positive control chemical known to require metabolic activation should also be used to ensure that the system is functioning properly. Without metabolic activation, a direct-acting positive control chemical should be used. A structurally related positive control can also be used. Appropriate safety precautions must be taken in handling clastogens (IARC, 1979 MRC, 1981). 

Induction of P-450 Metabolism and Isoenzymes. When organisms are exposed to certain xenobiotics their ability to metabolize a variety of chemicals is increased. This phenomenon can produce either a transitory reduction in the toxicity of a drug or an increase (if the metabolite is the more toxic species). However, this may not be the case with compounds that require metabolic activation. The exact toxicological outcome of such increased metabolism is dependent on the specific xenobiotic and its specific metabolic pathway. Since the outcome of a xenobiotic exposure can depend on the balance between those reactions that represent detoxication and those... 

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. 

Boyd MR, Statham CN, Longo NS. 1980. The pulmonary Clara cell as a target for toxic chemicals requiring metabolic activation studies with carbon tetrachloride. J Pharmacol Exp Ther212 109-114. 

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. 

Molecular modification can be used to eliminate the potential for toxicity from a candidate drug. This requires knowledge of the chemical mechanisms of toxic action, both direct and indirect (via metabolic activation), so that one may recognize the potential toxophore. 

Gehring PJ, Watanabe PG, Park CN. Resolution of dose-response toxicity data for chemicals requiring metabolic activation example-vinyl chloride. Toxicol AppI Pharmacol 1978 44(3) 581-591. 

Chemicals that require metabolic activation may be less toxic in neonatal animals as a result of reduced levels of enzyme activity. However levels of protection may also be reduced. 

Waters contaminated with appreciable levels of stable, potent mutagens that require metabolic activation for their shortterm effects. These chemicals appear primarily, if not exclusively, to be of industrial or agricultural origin. 

Water with relatively insignificant amounts of man-made chemicals but having appreciable TOC levels that yield mutagens as chlorination byproducts. These mutagenic mix-tines generally do not require metabolic activation but rather are less active when assayed +S9. 

Whether a toxin is naturally reactive to biological macromolecules or receptors, or requires metabolic activation to produce such a species, e.g. the enzyme-mediated transformation of tremorine (9) to the active parasympathomimetic agent oxotremorine (10), it will usually be subject to chemical or enzymic inactivation in vivo. Interruption of the latter process via appropriate substitution may thus lead to an increase in biological activity or toxicity over that of the parent compound. Perhaps the most striking example of this is provided by the extreme metabolic stability and toxicity of TCDD and the nontoxicity of its de- chloro analogue dibenzodioxin (Table 3). 

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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