Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA

Abstract

Since the pioneering work of the Millers it has become clear that most chemical carcinogens require metabolism to reactive electrophiles and then exhibit their carcinogenic potential by reacting chemically with, and modifying, cellular macromolecules. At first modification of proteins was considered most likely to be of importance in carcinogenesis. Later, Brookes and Lawley demonstrated that the extent of binding of several polycyclic hydrocarbons to DNA, but not to RNA or protein isolated from the skin of mice treated topically with these compounds, correlated with their known carcinogenic potency to this tissue. Mammalian cells, particularly mouse embryo cells, treated with chemical carcinogens have often been used, and DNA has been involved almost exclusively from whole cells. However, mitochondria possess unique DNA which accounts for 0.1-1% of the total DNA present in mammalian cells, and three studies have shown that carcinogenic alkylating agents modify the michondrial DNA by a factor about five times greater than the nuclear DNA from the same cells. We demonstrate here that with six polycyclic aromatic compounds, all of which require metabolic activation and bind to DNA to a much smaller extent than direct than direct-acting alkylating agents, the binding to mitochondrial relative to DNA is dramatically increased by a factor of nearly 50 to over 500.