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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 73; no. 8; pp. 2594 - 2598
• Main Authors: Yang, Shen K., McCourt, David W., Roller, Peter P., Gelboin, Harry V.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.08.1976; National Acad Sciences
• Subjects: Animals; Benzopyrenes - metabolism; Cell-Free System; Enantiomers; Epoxy compounds; Hydrolysis; Liver microsomes; Male; Metabolism; Metabolites; Microsomes; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; Molecular ions; Oxidases; Rats; Spectroscopy; Stereoisomerism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.73.8.2594

Benzo[a]pyrene is metabolically and stereo-specifically 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 predominantly the diol-epoxide, 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 the 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 both 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 diol-epoxides 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 ultraviolet absorption spectral analysis. The diol-epoxides were also reduced in the presence of NADPH to distinct trihydroxypentahydrobenzo[a]pyrenes. Since the synthetic racemic r7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene is very highly mutagenic in mammalian cells, we suggest that it is the metabolically formed diol-epoxide that may be an ultimate carcinogenic form of benzo[a]pyrene.