DNA Binding as a Probe for Metabolic Activation in Various Systems
The metabolic activation of chemical carcinogens has been studied intensively over the last 20 years. Classically, the pathway of activation was recognized by identifying a metabolite that exhibited greater carcinogenic potency than the parent carcinogen (1). For the polycyclic hydrocarbon carcinogens, this approach met with little success. However, theoretical chemists emphasized the K-regions as likely sites for interactions of these hydrocarbons with cellular components (2), and this theorization found a basis in the potent activity of hydrocarbon K-region oxides in various in vitro systems (3). As a result, there was a growing acceptance of these K-region oxides as the active forms of the hydrocarbon carcinogens, despite their very limited carcinogenic activities in in vivo animal test systems (4). The limited carcinogenic activity of these compounds was rationalized by the theory that their chemical reactivity led to their destruction before they reached the appropriate target cells or macromolecules.
KeywordsMicrosomal Protein Mouse Embryo Cell Hamster Liver Microsomal System Hydrocarbon Carcinogen
Unable to display preview. Download preview PDF.
- 1.Miller, E.C., and J.A. Miller. 1976. The metabolism of chemical carcinogens to reactive electrophiles and their possible mechanisms of action in carcinogenesis. In: Chemical Carcinogens. ACS Monograph 173. C.E. Searle, ed. American Chemical Society: Washington, DC. pp. 737–762.Google Scholar
- 4.Dipple, A. 1976. Polynuclear aromatic carcinogens. In: Chemical Carcinogens. ACS Monograph 173. C.E. Searle, Ed. American Chemical Society: Washington, DC. pp. 245–314.Google Scholar
- 8.Levin, W., A.W. Wood, P.G. Wislocki, R.L. Chang, J. Kapitulnik, H.D. Mah, Y. Yagi, D.M. Jerina, and A.H. Conney. 1978. Mutagenicity and carcinogenicity of benzo[a]pyrene and benzo[a]pyrene derivatives. In: Polycyclic Hydrocarbons and Cancer: Environment, Chemistry, and Metabolism, Volume 1. H.V. Gelboin, and P.O.P. Ts’o, eds. Academic Press: New York. pp. 189–202.Google Scholar
- 10.Moschel, R.C., W.M. Baird, and A. Dipple. 1977. Metabolic activation of the carcinogen 7,12-dimethylbenz[a]anthracene for DNA binding. Biochem. Biophys. Res. Comm. 76: 1092–1098.Google Scholar
- 17.King, H.W.S., M.H. Thompson, and P. Brookes. 1975. The benzo[a]pyrene deoxyribonucleoside products isolated from DNA after metabolism of benzo[a]pyrene by rat liver microsomes in the presence of DNA. Cancer Res. 34: 1263–1269.Google Scholar
- 19.Ames, B.N., J.McCann, and E. Yamasaki. 1975. Methods for detecting carcinogens and mutagens with the Salmonella/ mammalian-microsome mutagenicity test. Mutat. Res. 31: 347–364.Google Scholar