Abstract
Considerable evidence now points to 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrenes as ultimate mutagenic and carcinogenic forms of benzo(a)-pyrene. Quantum mechanical calculations have been performed to assess the possible general role of diol epoxides in polycyclic aromatic hydrocarbon (PAH) mutagenesis and carcinogenesis. The calculations enable a prediction of relative reactivity (ease of carbonium ion formation) for diol epoxides derived from a single PAH and also for diol epoxides from different PAHs. The calculated reactivity has so far been found to provide a good estimate of diol epoxide mutagenicity. Results of the metabolic activation of benzo(a)anthracene dihydrodiol derivatives and of the mutagenicity of benzo(a)anthracene diol epoxides are reported. Limitations inherent in predictions of polycyclic aromatic hydrocarbon carcinogenicity using a model based upon the calculated reactivity of a potential metabolite are discussed.
Zusammenfassung
Zahlreiche Beweise sprechen heute für 7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene als ultimale mutagene und carcinogene Formen des Benzo(a)pyrens. Quantenmechanische Berechnungen wurden durchgeführt, um die mögliche allgemeine Rolle von Diolepoxiden bei der Mutagenese und Carcinogenese von polyzyklischen aromatischen Kohlenwasserstoffen (PAH) abzuschätzen. Die Berechnungen ermöglichen eine Vorhersage der relativen Reaktivität (Leichtigkeit der Carboniumionenbildung) sowohl für Diolepoxide, die von einem einzelnen PAH abgeleitet sind, als auch für Diolepoxide von verschiedenen PAHs. Es wurde gefunden, daß die berechnete Reaktivität eine gute Abschätzung der Mutagenität von Diolepoxiden liefert. Ergebnisse über die metabolische Aktivierung von Benzo(a)anthracendihydrodiolderivaten und über die Mutagenität von Benzo(a)anthracendiolepoxiden werden berichtet. Vorhersagen der PAH-Carcinogenität mit Hilfe eines Modells, das auf der berechneten Reaktivität eines potentiellen Metaboliten basiert, unterliegen Beschränkungen, die diskutiert werden.
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Lehr, R.E., Jerina, D.M. Metabolic activations of polycyclic hydrocarbons. Arch. Toxicol. 39, 1–6 (1977). https://doi.org/10.1007/BF00343269
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DOI: https://doi.org/10.1007/BF00343269