Abstract
THE pioneering research by James and Elizabeth Miller relating the carcinogenic effects of many chemicals to the metabolism of these compounds to reactive intermediates which bind to critical cellular compoenents1,2 led to studies of the nature and chemical structure of these reactive metabolites (ultimate carcinogens) and their metabolic precursors (proximate carcinogens). The environmental carcinogen benzo[a]pyrene (BP) is metabolised by microsomal enzymes to arene oxides, phenols and dihydrodiols. Metabolic activation of the BP metabolite (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) by liver microsomes resulted in more binding to DNA than did the metabolic activation of BP (ref. 3). The reactive metabolite involved in the binding to DNA was a trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro BP (BP 7,8-diol-9,10-epoxide) (ref. 4). Both stereoisomers of this diol epoxide, which are enzymatically formed from BP 7,8-dihydrodiol (refs 5–8), were highly mutagenic to bacterial and mammalian cells9–15 suggesting that a BP 7,8-diol-9,10-epoxide might be an ultimate carcinogenic metabolite of BP. We report here that administration of BP 7,8-dihydrodiol to newborn mice caused more malignant lymphomas and pulmonary adenomas than did administration of benzo[a]pyrene. This is the first demonstration of a metabolite of a polycyclic aromatic hydrocarbon that is more carcinogenic than the parent compound. One of the stereoisomeric BP 7,8-diol-9,10-epoxides ((±)-trans-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydro BP; diol epoxide-2; also termed diol epoxide I (ref. 11) or anti-isomer (ref. 16)) produced about the same number of pulmonary adenomas as a 50-fold higher dose of BP.
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KAPITULNIK, J., LEVIN, W., CONNEY, A. et al. Benzo[a]pyrene 7,8-dihydrodiol is more carcinogenic than benzo[a]pyrene in newborn mice. Nature 266, 378–380 (1977). https://doi.org/10.1038/266378a0
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DOI: https://doi.org/10.1038/266378a0
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