Carcinogens Epoxide

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... 

In order to gain more detailed information about the physical binding of hydrocarbon metabolites to DNA, studies have also been carried out with model compounds which have many of the steric and electronic properties of carcinogenic epoxides but no reactive epoxide group. The use of nonreactive model compounds permits the clear separation of physical binding interactions from reactive interactions. Benzo[a]pyrene metabolite model compounds which have been examined include 7-hydroxy-7,8,9,10-tetrahydro-BP (4), and cis (4 ) and trans-7,8-dihydroxy-7,8,9,10-tetrahydro-BP (9). 

In addition to UV binding studies of BPDE, one other less carcinogenic epoxide, ( ) trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydro-BP, was examined. Table IV which contains results obtained in this study indicates that the intercalation binding constant is 23% lower than that of BPDE (3 ). 

Benz( )anthracene is also converted in the body to a carcinogenic epoxide (Eq. 27-28).793 Benzo(a)pyrene was isolated from coal tar in 1929 and in 1930 provided the first demonstration of the carcinogenicity of a pure chemical compound.794 It can also be activated by conversion in the ER to the 7,8-dihydrodiol 9,10-... 

Van Duuren BL. 1969. Carcinogenic epoxides, lactones, and halo-ethers and their mode of action. Ann NY Acad Sci 163 633-651. 

There is also some debate about whether the combination of valproate (especially valpromide) and carbamazepine should be avoided, not only because of the risk of toxicity but also because inhibition of epoxide hydrolase may be undesirable. This enzyme is possibly important for the detoxification of a number of teratogenic, mutagenic and carcinogenic epoxides. More study is needed. 

Other cases are described in Section 13.5 under the heading Lethal examples . Thus fluoroacetic acid is transformed to fluorocitric acid which blocks the enzyme aconitase. Several amines, such as benzidine and 2-aminonaph-thalene are converted to carcinogenic hydroxylamines and polycyclic hydrocarbons such as benzopyrene are converted to carcinogenic epoxides. The liver converts carbon tetrachloride to a free radical which causes liver necrosis (Slater, 1966). 

These studies have shown that benzo(a)pyrenes are not carcinogens as such, but that the carcinogenicity is developed due to their biotransformation into carcinogenic epoxide metabolites [51-56]. The two... 

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