Xenobiotic metabolism relevance to cancer.

Abstract

Xenobiotic metabolism—the double-edged sword It has been two decades since Wattenberg’s seminal review on the chemoprevention of cancer, cited over 900 times according to the ISI Web of Knowledge, subdivided cancer inhibitory agents into 3 broad categories (1). The classification scheme included 1) inhibitors of carcinogen formation from precursors, 2) agents that alter xenobiotic metabolism and protect against DNA damage, so-called ‘‘blocking’’ agents, and 3) ‘‘suppressing’’ agents that act postinitiation to prevent initiated cells from progressing to neoplasia. The review was important and timely and gave impetus to many subsequent studies on natural and synthetic chemopreventive agents. For example, .150 such agents have been tested against 1 chemical class alone, the cooked meat heterocyclic amines (2). From the outset, however, there were aspects of Wattenberg’s scheme that were viewed as a possible double-edged sword. Blocking agents that acted on a specific class of cytochrome P450 could, in principle, protect against certain carcinogens but enhance the metabolic activation of others. Phase 2 conjugations that were broadly viewed as ‘‘detoxification’’ reactions were known, in certain cases, to augment the activation and DNA reactivity of some chemical carcinogens. ‘‘Anticarcinogens’’ such as indole-3-carbinol also could act as promoters or tumorenhancing agents, depending on the testing protocols used in vivo (3). Ito et al. (4) referred to ‘‘stage dependent paradoxical effects’’ of agents that inhibited during the initiation phase but promoted postinitiation. Wattenberg believed that the most promising cancer chemopreventive agents were likely to be those in the suppressing agent category, because presumably most of us harbor initiated cells from an early age. However, he was quick to acknowledge that we lacked insight into the specific mechanisms that operated postinitiation, and as a result, few such agents had been identified, although the review article cited, among other compounds, retinoids and isothiocyanates as having some merit as later-stage preventive agents (1). This is noteworthy because of the knowledge that has accrued during the intervening 20 y, indicating that both classes of compounds affect gene expression, at least in part, via chromatin remodeling.