The Mammalian Detoxification System

Mammalian cells are continuously exposed to endogenous and exogenous toxins, either as by-products of metabolism or as environmental agents. These compounds are usually highly electrophilic and disrupt normal cellular function by reacting with nucleophilic centers located in and on proteins and DNA. In the extreme case, DNA adducts can be formed that result in the formation of a neoplastic cell and subsequently a cancerous cell can develop. To prevent these deleterious effects the mammalian system has developed specific pathways to stabilize and subsequently excrete xenobiotics. These pathways rely on the expression and activity of several groups of proteins known as Phase I and Phase II detoxification enzymes, such as cytochrome P450s [EC 1. 14.14.1], glutathione-S-transferases [EC], quinone reductase [EC], and UGT-glucoronosyltransferases [EC 2. 4.1.17]. The coordinate regulation of the latter group is generally controlled through the same transcriptional mechanism ensuring that several different Phase II detoxification enzymes may be induced by a single xenobiotic insult (112,113).

The association between Phase II detoxification enzymes and cancer risk has been the focus of much study. Deficiencies as a result of genetic polymorphisms can often lead to increased susceptibility to toxins and chemically induced carcinogenesis. These factors are emphasized in the reported increased susceptibility of smokers null for GST M1, GSTT1, and GSTP1 and additional associations with increased incidence of colon cancer, skin cancer, and ovarian cancers for individuals who are GSTM1-null (115119). One possible means to reduce cancer risk, representing the basic principle of chemoprevention, is to modulate the activities of cellular protective enzymes using dietary supplements or dietary intervention. An increased consumption of cruciferous vegetables containing ITCs that can potentially stimulate the induction of Phase II detoxification agents may offer aid in improving human health.

Inducers of Phase II detoxification enzymes are categorized in to two main groups based on the hypothesis first highlighted by Prochaska and Talalay (114). The first group, deemed bifunctional inducers, is comprised of chemical agents, such as polycyclic aromatics and h-napthoflavone, that induce gene expression either through the antioxidant responsive element (ARE) or xenobiotic-responsive element (XRE) present within the promoter region of many of these genes. In contrast, monofunctional inducers such as ITCs induce Phase II enzymes gene expression via the ARE. Of the several groups of enzymes studied the involvement and mechanisms for CYP450s, GSTs, and NQO1 have been widely addressed and it is these enzymes that will be the focus of discussion.

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