THE ROLE OF PAH-DNA ADDUCTS IN CAUSING CANCER

Abstract

This article addresses the evidence for the mechanism of activation of polycyclic aromatic hydrocarbons (PAH) to “ultimate carcinogenic” DNA-binding metabolites in cells and describes how analysis of DNA adducts allowed the determination that the metabolites are dihydrodiol epoxides of PAH. Initially, the PAH-DNA adduct analysis techniques we developed allowed us to establish that the reactive form of PAH that bind to DNA in cells was not the K-region epoxide. Further development of PAH-DNA adduct analysis techniques allowed us to determine that in the case of the very potent carcinogen dibenzo[a,l]pyrene, the reactive metabolite was a diol epoxide with “fjord region” of the molecule. Collaborative studies of DNA adducts in cells from a mouse in which cytochrome P450 1B1 levels were knocked out demonstrated that DB[a,l]P activation to DNA binding intermediates was reduced to undetectable levels demonstrating the great importance of this enzyme in activating fjord region containing PAH.

Keywords:

• DNA adducts
• dibenzo[a,l]pyrene
• cytochrome P450
• carcinogen

ACKNOWLEDGEMENTS

I gratefully acknowledge the many collaborators whose generous support and contributions made this work possible. Special thanks are due to Dr. Peter Brookes and Dr. Philip Grover, and the late Professor Peter Sims of the Institute of Cancer Research, London, England, for their contributions to these studies. I wish to thank the late Professor Charles Heidelberger of the McArdle Laboratories of the University of Missouri for graciously allowing me to attend his research group meetings to learn about PAHs while I was a graduate student working on phorbol ester tumor promoters with Professor R. K. Boutwell. Dr. Heidelberger's group meetings brought me into contact with many of the leading PAH researchers who later were of tremendous help in the development of my career including Drs. Grover and Brookes. I also want to thank all who very graciously provided the hydrocarbon derivatives used in many of these studies including Dr. Ronald G. Harvey of the University of Chicago; Dr. Shantu Amin of the American Health Foundation; Dr. Donald Jerina of the National Institutes of Health; Andreas Luch of the Institute of Toxicology and Environmental Hygiene, Technical University of Munich, Germany; and Albrecht Seidel of the Biochemical Institute for Environmental Carcinogens, Grosshansdorf, Germany. I wish to acknowledge the contributions of Dr. Brinda Mahadevan to the studies elucidating the role of P450 1B1 in the metabolic activation and mutagenic activity of DB [a,l] P. I also acknowledge the work of Daniel J. Albershardt in preparing the figures for this article and for his help in preparing the manuscript. Funding for much of this research was from the National Cancer Institute through Grants CA40228 and CA28825.