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A Kinetic Study on the in Vitro Covalent Binding of Polycyclic Hydrocarbons to Nucleic Acids Using Epidermal Homogenates as the Activating System¹

Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830

Several variables were studied in relation to the covalent binding of radioactive polycyclic aromatic hydrocarbon (PAH) tumor initiators to nucleic acids by epidermal aryl hydrocarbon hydroxylase in vitro. Initially, the binding of 3-methylcholanthrene (MC) to DNA was linear, although a leveling off was observed with increased concentrations of substrate, enzyme, DNA, and reduced nicotinamide adenine dinucleotide phosphate (NADPH). Covalent binding of MC and benzo(a)pyrene (BP) to DNA in vitro by an NADPH-dependent epidermal homogenate was linear for 90 min, after which it leveled off. A second addition of NADPH resulted in a linear increase in DNA binding lasting approximately 90 min more. At 12 hr after induction at various times with the corresponding unlabeled PAH, the specific activities of MC, BP, 7,12-dimethylbenz(a)anthracene, dibenz(a,h)anthracene, and dibenz(a,c)anthracene binding to DNA by epidermal homogenates in vitro all peaked. A correlation exists between the tumor-initiating ability of several PAH's and their ability to bind covalently to DNA in vitro with the use of mouse epidermal homogenates and NADPH as an electrophile-generating system [7,12-dimethylbenz(a)anthracene > MC > BP > dibenz(a,h) anthracene > dibenz(a,c)anthracene]. With the exception of DMBA, each of these PAH's possesses a strong need for NADPH. The specific activity of BP binding to various nucleic acids was: Polyguanylic acid > polyadenylic acid > yeast RNA > DNA.

¹ Supported in part by NIH Grant CA-20076 and by the Energy Research and Development Administration under contract with Union Carbide Corporation. By acceptance of this article, the publisher or recipient acknowledges the right of the United States Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

² Present address: University of Washington, School of Medicine, Seattle, Wash. 98195.

Received 3/ 3/77. Accepted 5/20/77.