Lipid carcinogens, activation

Free radical oxidation vivo has been much touted as a detriment to both health and life. Indeed, aberrant free radical reactions have been cited as contributors to aging (46, 47) and cancer (47, 48), but unequivocal evidence for these claims often is lacking. The connection between free radicals and the promotion of cancer has received the most attention. As discussed later, the evidence is compelling that lipid hydroperoxide activates certain carcinogens by cooxidation. 

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. 

Various chemicals, such as the fibrate (e.g., clofibrate, bezafibrate, and ciprofibrate) and other lipid-lowering drugs (e.g., Wy-14643) and phthalate plasticizers (e.g., diethylhexyl phthalate), bind to and activate PPARa and are also hepa to carcinogenic in rodents. However, different compounds bind with different affinities, from strong (e.g., Wy-14643) to weak (e.g., phthalates). Thus, it is believed that peroxisomal proliferators act via the receptor (PPARa) to cause some of the effects seen. 

Cutaneous biotransformation is mostly associated with the stratum basale layer where there can be phase I and phase II metabolism. However, the skin is not very efficient, compared to the liver. The epidermal layer accounts for the major portion of biochemical transformations in skin, although the total skin activity is low (2-6% that of the liver). Where activity is based on epidermis alone, that layer is as active as the liver or, in the case of certain toxicants, several times more active. For some chemicals, metabolism can influence absorption, and transdermal delivery systems of drugs utilize this activity. For example prodrug such as lipid esters are applied topically, and cutaneous esterases liberate the free drug. These basal cells and extracellular esterases have been shown to be involved in detoxification of several pesticides and bioactivation of carcinogens such as benzo(a)pyrene. For rapidly penetrating substances, metabolism by the skin is not presently considered to be of major significance, but skin may have an important first-pass metabolic function, especially for compounds that are absorbed slowly. 

The antagonism or prevention of toxic effects may also benefit from stereochemical principles. Thus, optically active flavanones have been shown to inhibit the metabolic activation of the carcinogen benzo[a]pyrene to metabolites that bind covalently to DNA (Chae et al., 1992). Moreover, the (+) enantiomers of 3-0-methyicatechin and catechin have been demonstrated to protect stereoselectively against lipid peroxidation due to paracetamol (Devalia et al., 1982),... 

Peroxides can play a physiological role in the cell but also mediate processes leading to heart disease and carcinogenesis. Fatty acid peroxidation may also be related to free radical-mediated metabolic activation of carcinogens or drugs, which lead to the initiation of carcinogenesis or cytotoxicity. Modification of membrane function as a consequence of lipid peroxidation includes imcoupling of oxidative phosphorylation... 

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