Pro-oxidant and anti-oxidant mechanism(s) of BHT and beta-carotene in photocarcinogenesis.

An hypothesis for the role of free radicals in cancer was elaborated by D. Harman in 1962 who suggested that it might be possible to reduce the extent of damage caused by free radicals through three dietary changes: (i) caloric reduction, i.e., lowering the level of free radical reactions arising in the course of normal metabolism; (ii) minimize dietary components that tend to increase the level of free radical reactions (e.g., polyunsaturated fats); and (iii) supplement the diet with one or more free radical reaction inhibitors (anti-oxidants). With respect to (ii) and (iii), lipid peroxidation exemplifies the type of chain reaction initiated by free radicals, with unsaturated fatty acids being the primary center of free radical attack. Anti-oxidants act as free radical scavengers and are able to terminate these reactions. Indeed, the phenolic anti-oxidant butylated hydroxytoluene (BHT), and the carotenoid beta-carotene, have both been shown to influence photocarcinogenesis, although the lack of correlation between physicochemical parameters and pathophysiological responses is apparent in both instances. The bimolecular rate constant for reaction of BHT with model peroxyl radicals is low while beta-carotene is highly reactive. However, both are able to efficiently inhibit lipid peroxidation reactions in biological membranes. Indeed, the influence of photocarcinogenesis by both BHT and beta-carotene is diminished as the level of dietary fat decreases, pointing to the involvement of lipid peroxidative reactions. Nevertheless, the mode of action of BHT in inhibiting photocarcinogenesis appears to be related to dose-diminution resulting from an increased spectral absorbance of the stratum corneum. On the other hand, beta-carotene has no such effect and may actually exacerbate photocarcinogenesis under certain dietary conditions. This paradox points to the complex relationship between chemical mechanisms and biological mode of action of anti-oxidants in photocarcinogenesis. Recent clinical and experimental data also suggest that supplementation of the complex and intricately balanced natural antioxidant defense system with one or more anti-oxidants as a cancer prevention strategy will demand extreme caution.