Mammalian Epoxide Hydrases: Inducible Enzymes Catalysing the Inactivation of Carcinogenic and Cytotoxic Metabolites Derived from Aromatic and Olefinic Compounds

8,9‐Dihydro‐8,9‐dihydroxybenz(a)anthracene 10,11‐oxide: A new type of polycyclic aromatic hydrocarbon metabolite

“…The major, faster moving product exhibited the chromatographic properties of the syntheticallyprepared 10,ll -oxide in three chromatographic systems. The more polar product is probably the 8,9, IO.11 -tetrahydrotetrol derivative formed by the further metabolism of the 10,ll -oxide, since epoxides are hydrated to dihydrodihydroxy derivatives by microsomal 'epoxide hydrase' [4] . This is supported by the finding that more of the polar metabolite is present in incubation mixtures that do not contain the 'epoxide hydrase' inhibitor, cyclohexene oxide [4] (table 2).…”

“…The more polar product is probably the 8,9, IO.11 -tetrahydrotetrol derivative formed by the further metabolism of the 10,ll -oxide, since epoxides are hydrated to dihydrodihydroxy derivatives by microsomal 'epoxide hydrase' [4] . This is supported by the finding that more of the polar metabolite is present in incubation mixtures that do not contain the 'epoxide hydrase' inhibitor, cyclohexene oxide [4] (table 2). Table 2 also demonstrates that microsom~ oxidation of the isolated IO,1 1 -bond of the 8,9-dihydrodiol is an enzymic reaction that requires NADPH.…”

“…These metabolites arise by the action of microsomal monooxygenases on the aromatic double bonds which forms epoxide intermediates [2,3] that are subsequently converted into dihydrodiols by microsomal 'epoxide hydrase' [4] or into glutathione conjugates by the soluble 'glutathione S-epoxide transferase' [5] . The dihydrodiols are themselves further metabolized by rat-liver preparations to intermediates that yield ~utathione conjugates in the presence of the 'transferase [6].…”

Transplacental control of epoxide hydratase and its relationship to the control of microsomal monooxygenase

“…Such alterations of important biomacromolecules can involve disturbancies of the ordered sequences and interrelationships of biochemical events in a cell in such a way as to lead to mutagenicity, carcinogenicity or cell necrosis (for a review see [l] ). In the subcellular compartment were these epoxides are formed, the endoplasmatic reticulum, they can be metabolized by epoxide hy.lratase(s) (EH) (EC 4.2.1.63) to much less reactive dihydrodiols (for a review see [2] ; for reactivation of a dihydrodiol by epoxidation at another site, and inactivation of the resulting mixed dihydrodiol-epoxide by epoxide hydratase-catalyzed transformation to a tetrahydrotetrol see [3,4]). Induction of EH would therefore be of great experimental and possibly practical interest, especially if MO responsible for the formation of epoxides, was not concomitantly induced.…”

Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxy-anisole and other phenols on hepatic enzyme activities in mice

“…Wattenberg et al (1980) have already shown that feeding of 4-methoxyphenol and 3-t-butyl-4-hydroxyanisole (the minor isomer of BHA) to mice resulted in a 75%o drop in BaP induced tumours of the forestomach while the feeding of equimolar amounts of 2-t-butylphenol, 2,6-di-t-butylphenol, t-butyl-hydroquinone and 2-tbutyl-4-hydroxyanisole (the major isomer of BHA) resulted in a 40-50%0 drop in the incidence of neoplasia. According to Oesch (1972) (Oesch, 1972), its protective role in BaP-induced neoplasia is questionable, because it is the enzyme responsible for converting BaP-7,8-epoxide into BaP-7,8-dihydrodiol, the precursor of the ultimate carcinogen, BaP-7,8-diol-9, 10-epoxide (Kahl et al, 1978;Guenthner & Oesch, 1981). There appears to be a modest correlation between GSH 8-transferase inducibility (Table IV) and protection against BaP-induced neoplasia (Wattenberg et al, 1980).…”