Epoxides, carcinogenicity

This epoxidation of AFB has been associated with aldrin epoxidase (AE) activity in trout (30). As with other epoxide carcinogens, OAFB may be a substrate 7or epoxide metabolizing enzyme systems such as epoxide hydrase (EH) (EC4.2.1.63) and glutathione-S-epoxide transferase (GTr) (EC4.4.1.7) found in mammals and fish (31, 32, 33, 34). AFB also undergoes a variety of other reactions, generally to less toxic metabolites depending on the species of animal involved (35, 36). The primary AFB metabolite in rainbow trout has been shown to be a reduced form of AFB, aflatoxicol (AFL) (24). 

Figure 14.14 Benzenoid aromatic hydrocarbons. Some polycyclic aromatic hydrocarbons (PAHs), such as dibenzo[a,Qpyrene, are carcinogenic. (See "The Chemistry of. . . Epoxides, Carcinogens, and Biological Oxidation" in Section 11.14.)...

Many naturally occurring substances are epoxides You have seen two examples of such compounds already m disparlure the sex attractant of the gypsy moth (Section 6 18) and m the carcinogenic epoxydiol formed from benzo[a]pyrene (Section 118) In most cases epoxides are biosynthesized by the enzyme catalyzed transfer of one of the oxy gen atoms of an O2 molecule to an alkene Because only one of the atoms of O2 is trans ferred to the substrate the enzymes that catalyze such transfers are classified as monooxy genases A biological reducing agent usually the coenzyme NADH (Section 15 11) is required as well... 

Dmg metaboHsm may also produce toxic materials. Thus, the aromatic hydroxylation of hydrocarbons such as ben2pyrene produces the highly reactive and carcinogenic 1,2-epoxides. 

Some laboratory studies with rats and mice have linked trichloroethylene exposure to various types of cancers. Several of these studies, however, should be viewed cautiously, since the tumorigenic activity might be influenced by the presence of direct-acting compounds, namely the epoxides (e.g., epichlorohydrin) added as stabilizers in trichloroethylene. Epoxides are known to be very reactive, and some, such as epichlorohydrin, are potent carcinogens themselves. 

Animal studies have shown that tumors can result from both inhalation (Fukuda et al. 1983 Henschler et al. 1980 Maltoni et al. 1986) and oral exposure (Aima et al. 1994 Henschler et al. 1984 NCI 1976 NTP 1990) to trichloroethylene. Unfortunately, some of these studies (NCI 1976) are limited in that they use carcinogenic epoxide stabilizers with the trichloroethylene, which may contribute to the carcinogenicity. The studies also show different responses depending on the sex, species, and strains of animals used and do not point to a particular target organ for increased tumor incidence. Other studies are flawed because of excess... 

Henschler D, Elsasser H, Romer W, et al. 1984. Carcinogenicity study of trichloroethylene, with and without epoxide stabilizers, in mice. J Cancer Res Clin Oncol 107 149-156. 

Lee H, RG Harvey (1986) Synthesis of the active diol epoxide metabolites of the potent carcinogenic hydrocarbon 7,12-dunethybenz[a]anthacene. J Am Chem Soc 51 3502-3507. 

Research in PAH carcinogenesis has made major advances in the past decade. Most notable has been identification of diol epoxide metabolites as the active forms of benzo[a]pyrene, 7,12-dimethylbenz[tf]anthracene, and other carcinogenic PAH. This finding has stimulated enormous research activity and opened the way to determination of the detailed molecular mechanism of action of this important class of carcinogenic molecules. 

The structure-activity considerations at that time naturally enough focussed interest on epoxides formed at the K-regions of the carcinogenic hydrocarbons (Figure 3), but it was not until 1964 that the synthesis of such putative metabolites was achieved (46). 

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