Reaction of nontoxic, potentially chemopreventive purinethiols with a direct-acting, electrophilic carcinogen, benzo[a]pyrene-7,8-diol 9,10-epoxide

Several nontoxic purinethiols have been shown to block the ability of the carcinogen 7-r,8-t-dihydroxy-9-t,10-t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) to bind covalently to DNA in Chinese hamster ovary cells. Two of these compounds also block BPDE-induced tumorigenesis in a two-stage mouse ski...

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Bibliographic Details
Published in:Chemical research in toxicology 1993-03, Vol.6 (2), p.159-167
Main Authors: MacLeod, Michael C, Qing, Wei Guo, Powell, K. Leslie, Daylong, Anne, Evans, Frederick E
Format: Article
Language:English
Subjects:
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - chemistry
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - chemistry
Chemical agents
DNA - metabolism
Hydrogen-Ion Concentration
Kinetics
Magnetic Resonance Spectroscopy
Medical sciences
Octanols
Purines - chemistry
Sulfhydryl Compounds - chemistry
Temperature
Tumors
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Summary:Several nontoxic purinethiols have been shown to block the ability of the carcinogen 7-r,8-t-dihydroxy-9-t,10-t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) to bind covalently to DNA in Chinese hamster ovary cells. Two of these compounds also block BPDE-induced tumorigenesis in a two-stage mouse skin carcinogenesis model. The suggested mode of action of the purinethiols is through scavenging the electrophilic carcinogen by way of covalent reaction with the purinethiol. In the present work, we demonstrate that a series of five purinethiols (2,6-dithiopurine, thiopurinol, 6-thioxanthine, 2-mercaptopurine, and 9-methyl-6-mercaptopurine) react covalently in vitro with BPDE. The adducts formed have been characterized by UV-visible spectroscopy, solvent partitioning, and NMR spectroscopy; they result from addition of the thiol moiety at the 10-carbon of BPDE. Studies of the effects of Tris buffer and temperature on product ratios at completion of reaction indicate that the two major reaction pathways, hydrolysis of the epoxide and adduct formation, do not share a common rate-determining step. This suggests that the reaction mechanism for adduct formation is through SN2 attack of the thiol moiety at the 10 position of BPDE. The activation energies for the reaction of 5-purinethiols with various combinations of substituents at the 2 and 6 positions are all very similar, implying closely similar transition states. For compounds with a low pKa (2,6-dithiopurine, 2-mercaptopurine, and 6-thioxanthine) the most important reactant at physiological pH is the thiolate anion. However, for compounds with pKa's above 8, the physiologically important reactions appear to be more complicated.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx00032a004