Dietary Factors May Modify Cancer Risk by Altering Xenobiotic Metabolism and Many Other Mechanisms

The frequently asked question is ‘‘What is the relationship between alteration in xenobiotic metabolism and cancer risk?’’ Based on the two expanded abstracts by Drs. J. S. Felton and R. H. Dashwood as well as many publications, we can answer the question by stating: Dietary manipulations that alter xenobiotic metabolism leading to decreased carcinogen activation and enhanced carcinogen elimination are expected to reduce cancer risk. We also know that a specific chemical may affect the metabolism of different carcinogens differently, and dietary chemicals may trigger other molecular events that could decrease or increase cancer risk. Therefore, information on the biological effects of dietary substances based on inadequate or inappropriate studies on biomarkers could be misleading. Carcinogen metabolism was an active area of research in the 1970s and 1980s. In many earlier studies on the effects of dietary factors on carcinogenesis, carcinogen metabolism was a key target for study, and indeed, many dietary chemicals were found to affect Phase I (mainly cytochrome P450 enzymes) and Phase II xenobiotic metabolism enzymes (1,2). For example, inhibition of cytochrome P450-catalyzed carcinogen activation has been proposed as the mechanism of cancer prevention by organosulfur compounds such as diallyl sulfide and phenethyl isothiocyanates (2). Induction of Phase II enzymes that enhance the elimination of carcinogens has been proposed as the chemopreventive mechanism for sulforaphane and other compounds (3). However, recent studies also showed that these isothiocyanate compounds have other biological activities, such as induction of apoptosis and inhibition of histone deacetylase (4,5). Indeed, many mechanisms of cancer preventive activity by dietary chemicals proposed in recent years are not related to carcinogen metabolism. These data were obtained when dietary chemicals were administered to animals in the postinitiation stage, that is, when the animals were no longer exposed to carcinogens or in studies with genetically modified mice in which exposure to carcinogens was not needed. In these studies, even for a single compound, many mechanisms have been proposed, including many signal transduction pathways that are related to cell proliferation, apoptosis, and angiogenesis. How do we determine which of the mechanisms are relevant and which are irrelevant for cancer prevention? This will be the topic of the remaining part of this article.