TY - JOUR
T1 - The approach to understanding aromatic hydrocarbon carcinogenesis. The central role of radical cations in metabolic activation
AU - Cavalieri, Ercole L.
AU - Rogan, Eleanor G.
N1 - Funding Information:
Acknowledgements--Preparation of this review was supported by U.S. Public Health Service grants POI CA49210, RO1 CA25176, RO1 CA44686 and RO1 CA49917. These advances in PAH carcinogenesis have been made possible by key scientists in our research group, as well as our collaborators. We thank the members of our research group: Drs P. Cremonesi and N.V.S. RamaKrishna who studied radical cation chemistry and synthesized adducts; Dr RamaKrishna who also analyzed biologically-formed depurination adducts; Dr P. Devanesan who performed the biological experiments and analyzed stable adducts; Ms S. Higginbotham who conducted the tumorigenicity experiments in mice and rats. We thank our collaborators Drs G. J. Small and R. Jankowiak of Iowa State University for the essential identification of biologically-formed adducts by fluorescence line narrowing spectrometry and Drs M. L. Gross and R. L. Cerny, Midwest Center for Mass Spectrometry, University of Nebraska-Lincoln, for identification of adduct structures by mass spectrometry.
PY - 1992
Y1 - 1992
N2 - Polycyclic aromatic hydrocarbons (PAH) are carcinogens requiring metabolic activation to react with cellular macromolecules, the initial event in carcinogenesis. Cytochrome P450 mediates binding of PAH to DNA by two pathways of activation. One-electon oxidation to form radical cations is the major pathway of activation for the moset potent carcinogenic PAH, whereas monooxygenation to form bay-region diol epoxides is generally a minor pathway. For benzo[a]anthracene, 80% and 99%, respectively, of the DNA adducts formed by rat liver microsomes or in mouse skin arise via the radical cation. Therefore, studies of PAH activation should begin by considering one-electron oxidation as the primary mechanism.
AB - Polycyclic aromatic hydrocarbons (PAH) are carcinogens requiring metabolic activation to react with cellular macromolecules, the initial event in carcinogenesis. Cytochrome P450 mediates binding of PAH to DNA by two pathways of activation. One-electon oxidation to form radical cations is the major pathway of activation for the moset potent carcinogenic PAH, whereas monooxygenation to form bay-region diol epoxides is generally a minor pathway. For benzo[a]anthracene, 80% and 99%, respectively, of the DNA adducts formed by rat liver microsomes or in mouse skin arise via the radical cation. Therefore, studies of PAH activation should begin by considering one-electron oxidation as the primary mechanism.
UR - http://www.scopus.com/inward/record.url?scp=0027093718&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027093718&partnerID=8YFLogxK
U2 - 10.1016/0163-7258(92)90015-R
DO - 10.1016/0163-7258(92)90015-R
M3 - Article
C2 - 1289900
AN - SCOPUS:0027093718
SN - 0163-7258
VL - 55
SP - 183
EP - 199
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 2
ER -