Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Abstract

Benzo[a]pyrene is metabolically and stereospecifically converted by mixed function oxidases of rat liver microsomes and epoxide hydratase [glycol hydro-lyase (epoxide-forming), EC 4.2.1.63] to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzo[a]pyrene. This enantiomer is further metabolized stereoselectively by the mixed function oxidases to the diolepoxide, r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in which the 7-hydroxyl and the 9,10-epoxide are trans. Other unidentified metabolites are also formed from r-7,t-8-dihydroxy-7,8-dihydrobenzo[a]pyrene. Racemic r-7,t-8-dihydroxy-7,8-dihydrobenzo[a]pyrene is converted metabolically to r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene. The diolepoxides are unstable in aqueous medium, and their identification and characterization as r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene were accomplished by the identity of their tetrahydroxytetrahydrobenzo[a]pyrenes hydrolysis products with those of the authentic synthetic compounds with respect to mobility on high pressure liquid chromatography and mass and UV absorption spectral analysis. The diolepoxides were also reduced in the presence of NADPH to distinct trihydroxypentahydrobenzo[a]pyrenes. Since the synthetic racemic r-7, t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene is mutagenic in mammalian cells, it is the metabolically formed diolepoxide that may be an ultimate carcinogenic form of benzo[a]pyrene.