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.

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples

“…mtDNA is thought to be more susceptible to mutations for the following reasons: (i) it is not protected by histone molecules like chromosomal DNA, 15,16 (ii) mitochondria are a source of oxygen radicals which can cause oxidative DNA damage 17 and (iii) DNA polymerase gamma copies mtDNA with poor fidelity. 18 Besides speculations about a functional role of mitochondria in cancer, somatic mtDNA mutations may reflect enhanced oxidative DNA damage in tumors, probably also affecting nuclear genes.…”

A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

“…The accumulation of deleterious mutations in the mitochondrial genome has also been proposed to be important in aging (2)(3)(4)(5). It was known that some types of DNA damage occur at higher levels in mitochondrial DNA (mtDNA) and that mitochondria are deficient for some types of DNA repair; some repeated nuclear sequences also show such a deficiency (11)(12)(13)(14). But assays with the sensitivity to detect the basal level of some types of mitochondrial mutation in normal human tissues have only recently been developed (5,15,16).…”

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

“…Yakes e Van Houten 198 relataram que os danos ao DNA mitocondrial são mais extensos e persistem por mais tempo que os danos ao DNA nuclear em fibroblastos humanos submetidos a estresse 201 e que este é mais susceptível que o nuclear à alquilação 202,203 . Niranjan et al 204 demonstraram que a administração do carcinógeno hepático aflatoxina B1 a ratos resulta em ligação covalente ao DNA mitocondrial do fígado em concentrações de três a quatro vezes maiores que ao DNA nuclear, permanecendo inalterada mesmo após 24 horas.…”

“…A toxicidade de agentes oxidantes sobre a mitocôndria e seu DNA também tem sido relacionada ao processo carcinogênico 198,200 . Outros fatores como a reação preferencial de carcinó-genos com DNA mitocondrial em relação ao nuclear 201,202,204,205 e a relação direta entre a potência carcinogênica de uma série de N-hidroxiacetilaminofluorenos em ratos e sua capacidade de afetar a fosforilação oxidativa 222 , também têm indicado que a mitocôndria pode exercer um papel importante nos danos celulares quimicamente induzidos e relacionados com o o desenvolvimento do câncer.…”