Tumor-initiating activity of the (+)-(S,S)- and (-)-(R,R)-enantiomers of trans-11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene in mouse skin

A single administration of enantiomerically pure 11,12-dihydrodiols of dibe nzo[a,l]pyrene (DB [a,l]P) on the back of NMRI mice and subsequent chronic treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) (initiation/promo tion assay) revealed strikingly different carcinogenic activities of both e nantiomers. Tumor-initiating activity of (-)-(11R,12R)-DB[a,l]P-dihydrodiol , which is the metabolic precursor of the (-)-anti-(11R,12S)-dihydrodiol (1 3S,14R)-epoxide, was exceptionally higher than the corresponding effect of (+)-(11S,12S)-DB[a,l]P-dihydrodiol, the metabolic precursor of (+)-syn-(11S ,12R)-dihydrodiol (13S,14R)-epoxide. After topical application of 10 nmol ( -)-11,12-dihydrodiol and promotion with TPA twice weekly for a further 18 w eeks 93% of treated animals exhibited four to five tumors. In contrast, no neoplasms were observed after treatment with 10 nmol (+)-11,12-dihydrodiol, whereas in the group exposed to 20 nmol of this enantiomer only 13% of mic e developed neoplasms (0.1 tumors/survivor). For DB[a,l]P, considered as th e most potent carcinogenic polycyclic aromatic hydrocarbon to date, stereos elective formation of (+)-syn- and (-)-anti-11,12-dihydrodiol 13,14-epoxide s via the corresponding enantiomeric 11,12-dihydrodiols has been found to b e the principal metabolic activation pathway leading to DNA adducts and mut agenicity. Our study demonstrates that the striking difference in carcinoge nic activity in mouse skin of (+)-(11S,12S)- and (-)-(11R,12R)-DB [a,l]P-di hydrodiol convincingly reflects the different genotoxicity, i.e. DNA bindin g and mutagenicity, of both enantiomers observed earlier. (C) 1999 Publishe d by Elsevier Science Ltd. All rights reserved.