Many chemicals require metabolic activation in order to exert their carcinogenic potential. The pioneering studies of Elizabeth and James Miller showed that metabolic activation of azo dyes led to their covalent binding to cellular macromolecules. They went on to show with the model carcinogen 2-acetylaminofluorene that hydroxyla-tion of the amide nitrogen generated a metabolite that was more carcinogenic than the parent molecule. Subsequently it was found that these primary products of metabolism, although activated, could be further metabolized to even more reactive derivatives (Miller, J. A., 1970 and Miller, E. C., 1978). It was the Millers who understood that these products were potent electrophiles and comprehensively described their rapid covalent interactions with cellular macromolecules (Miller and Miller, 1981). This led to their proposal that chemical carcinogens that require such metabolic conversion in order to exert their carcinogenic effect should be called procarcinogens and that their highly reactive electrophilic metabolites were ultimate carcinogens. This further led to the concept of proximal carcinogens (e.g. ^-hydroxy-2-acetylamino-fluorene), which were intermediates between the parental procarcinogen and the ultimate carcinogenic metabolite. Although this concept has now been with us for more than two decades, the structure of many ultimate carcinogens is still not thoroughly understood and in many cases may comprise a number of different metabolites of the same parent compound.
There are a number of these metabolic pathways that together are part of a more extensive defence system, the overall role of which is ideally to process and detoxify noxious chemicals. Enzyme-catalysed and diverse in nature, these reactions have been defined and split into what are called phase I and phase II metabolism (Williams, 1971). Phase I can be separated into oxidation, reduction and hydrolytic reactions and phase II comprises a series of conjugation reactions in which a polar endogenous group is added to the xenobiotic chemical. The overall effect of this biochemistry is to convert xenobiotics, which are often lipophilic molecules, into more polar water-soluble and therefore more readily excreted products. Generally, phase I reactions unmask or introduce a functional group into the molecule and phase II metabolism conjugates the derivative with a polar water-soluble endogenous molecule, that is often acidic in nature. However, it is these same pathways of detoxification metabolism that can inadvertently bioactivate chemical carcinogens. For a more detailed description of phase I and phase II metabolism reactions and associated enzymology, the reader is directed to Jakoby et al. (1982), Parkinson (1996) and Gonzalez (1989).
The majority of procarcinogens are activated by mechanisms involving two-electron-mediated metabolic reactions primarily catalysed by the mixed function oxidase enzyme systems, often involving cytochrome P-450 enzymes. However, a number of one-electron reactions are known to be capable of activating xenobiotics in co-oxidation processes. For example, PAHs have been found to be bioactivated during the synthesis of prostaglandins from arachidonic acid. A key enzyme in this process is prostaglandin H synthetase, which catalyses the oxygenation of arachidonic acid to the endoperoxide prostaglandin G2 and also has peroxidase activity, whereby it reduces the hydroperoxide prostaglandin G2 to the alcohol prostaglandin H2. In these reactions the peroxidase activity of the enzyme yields a free radical product that can donate electrons to xenobiotics (Eling et al., 1990). Other enzyme systems which can participate in these one-electron activation reactions include constitutive peroxidases such as myeloperoxidase and lactoperoxidase, both of which are capable of activating xenobiotics. Although these co-oxidation pathways are not as quantitatively important as the mixed-function oxidase activities, their presence in tissues that lack mixed function oxidase activity can be an important contributor to xenobiotic activation.
Was this article helpful?
Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.