Epoxide hydrolase stereospecificity

It was shown that microsomal epoxide hydrolase-catalyzed trans-addition of water to BaP 9,10-epoxide occurs stereospecifically at the C-9 position (15). Since BaP is metabolized essentially to an optically pure 9R,10R-dihydrodiol (13 and L5 Table I), the 9,10-epoxide formed in BaP metabolism must have 9S,10R absolute stereochemistry (Figure 1). Similarly, the 7,8-epoxide formed in BaP metabolism is hydrated specifically at the C-8 position to form the 7R,8R-dihydrodiol (14.21). Hence the enzymatically formed 7,8-epoxide intermediate has 7R,8S absolute stereochemistry (Figure 1). Although the 7R,8R-dihydrodiol is formed almost exclusively from BaP metabolism in rat liver microsomes (Table I) and in bovine bronchial explants (25). the 7S,8S-dihydrodiol is also formed from BaP metabolism in mouse skin epidermis in vivo (5). 

As with several other functional groups considered earlier, epoxides are most commonly found in alkaloid metabolites rather than the original compound. These epoxides may arise via oxidation of alkenes or aromatic hydrocarbons. Epoxide hydrolase catalyzes hydrolysis of epoxides to the more hydrophilic diol. As seen in Scheme 6, this is usually a stereospecific reaction that always yields a... 

The stereospecific metabolism of racemic benzo [a] pyrene 4,5-, 7,8-, and 9,10-oxides (28, 366, and 367, respectively) by rat liver microsomes or highly purified epoxide hydrolase has been examined by Thakker et al.22 The optical purity of the metabolically formed benzo [a] pyrene 7,8- and 9,10-dihydrodiols is relatively low (8 and 22%, respectively). The metabolically formed benzo [a] pyrene-4,5-dihydrodiol is highly enriched in the (—) enantiomer (78% optical purity). The low optical purity of benzo [a] pyrene-7,8-dihydrodiol is attributed to the ability of epoxide hydrolase to act upon position 8 of both optical isomers of 366 with almost equal ease. 

Rearrangement of the epoxides to phenols competes with hydration to dihyd-rodiols. The hydration is catalyzed by the microsomal enzyme epoxide hydrolase 362). Dihydrodiols are not formed in the absence of epoxide hydrolase or in the presence of inhibitors of epoxide hydrolase such as l,l,l-trichloro-2,3-propene oxide (TCPO) 138, 203, 417). The dihydrodiols are formed stereospecifically from the 4,5-, 7,8-, and 9,10-epoxides as the (—)-trans isomers 416, 506). 

---