Species Heterogeneity in the Metabolic Processing of Benzo[a]pyrene
The detoxification response of the organism toward chemical carcinogens is to transform these potentially toxic compounds into more polar, less lipid soluble substances that are readily excretable and therefore harmless. However, it would appear that nature has made a serious mistake in the case of chemical carcinogens. This concept can be stylized by superimposing the steps in metabolic activation upon a chemical energy activation diagram (see Figure 1). It is generally assumed that the parent molecules of an environmentally prevalent chemical carcinogen are structurally stable and relatively inactive metabolically. This assumption is not unreasonable from a teleological point of view since one would expect labile chemical substances to be rapidly degraded or oxidized, due to sunlight and weather, if released in the open environment. Synthetically prepared activated carcinogens, such as polyaromatic epoxides and nitrosamines, have been shown to possess very short half-lives under physiological conditions. Therefore, the parent compound undergoes a decrease in entropy to increase its potential energy for subsequent metabolic degradation. This change requires enzymatic transformation into a reactive intermediate antecedent to further catabolism. Current evidence shows that all known carcinogenic chemicals are electrophilic reagents that seek out nucleophilic sites inside the cells (1). The peak of the curve in Figure 1 is the zone where the electron-deficient reactive metabolite is thought to interact with nucleophilic target sites hypothesized to begin the process of malignant transformation. If no such interaction takes place, the most common reaction is hydroxylation to form a metabolically inactive polar structure that is more hydrophilic and can be readily excreted. Therefore, the major thrust of the detoxification process is to render the parent compound into a structure of greater entropy and consequently less potential to exert a toxic effect.
KeywordsChemical Carcinogen Polycyclic Hydrocarbon Detoxification Response Lipid Soluble Substance Hepatic Microsomal Metabolism
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