Lecture 2b - Spontaneous decomposition of DNA: Oxidation...

Info iconThis preview shows pages 1–6. Sign up to view the full content.

View Full Document Right Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Spontaneous decomposition of DNA: Oxidation through natural processes The Oxygen Paradox: oxygen is dangerous for us even though it is an essential component of energy production defense against oxygen toxicity in mammals is sharp gradient of oxygen tension from environmental level of 20% to 0.5 to 5% oxygen concentration in tissues increasing oxygen tension can lead to DNA damage Pathways for intracellular oxidant generation Generation of reactive oxygen species (ROS) via reduction of molecular oxygen O 2 + e- O 2- (superoxide anion) O 2- + H 2 O HO 2 (hydroperoxyl radical) HO 2 + e- + H H 2 O 2 (hydrogen peroxide) H 2 O 2 + e- OH - + OH (hydroxyl radical) Endogenous sources of ROS: m ito c ho ndria , c yto c hro m e P450, m ac ro pha g e /inflam m a to ry c e lls Exogenous sources of ROS: P450 m e ta bo lis m o f c e rta in drug s a nd to xic c o m po unds s uc h as lindane , TC DD, phe no ba rb ita l e nviro nm e nta l a g e nts c a n dire c tly c o ntrib ute to the fo rm a tio n o f RO S s uc h as m e tal io ns , c hlo rina te d c o m po unds , radiatio n.. Cellular antioxidants: Enzym a tic : s upe ro xide dis m utas e , c ata las e , g luta thio ne pe ro xida s e , g lutare do xin, thio re do xin No ne nzym atic : vita m in E, g luta thio ne , vita m in C , c ate c hins Oxidation and compartmentalization of DNA nucleus is poorly oxygenated intracellular compartment lacks detectable O 2 metabolism metabolism of reactive oxygen to mitochondria could be seen as serving to protect nuclear DNA against oxidative DNA damage (evolution?) but mitochondria also have DNA would expect that mitochondrial DNA would be more likely to acquire oxidative damage histones quench generation of oxygen radical-inflicted DNA damage, mitochondrial DNA doesnt have histones Oxidation of DNA bases formation of thymine glycols: formation of formamidopyrimidines formation of 8-hydroxyguanines.. 8-hydroxyguanine oxidation of guanine residues to 8-hydroxyguanine major mutagenic base lesion generated by hydroxyl radicals is 8-hydroxyguanine, which base- pairs preferentially with adenine ra the r tha n cytosine : g e ne rate s tra ns ve rs io n m uta tio ns a fte r re plic a tio n cytosine deamination and oxidation of 8-hydroxyguanine are the two major forms of spontaneous directly premutagenic events in living cells both occur at similar frequencies each type of event takes place 100-500 times per day in a human cell levels of 8-ohG are higher in mitoDNA than nuclear DNA, and even higher in mitochondria exp to oxidative stress Alkylation damage introduction...
View Full Document

This note was uploaded on 12/03/2010 for the course PHAMACOLOG pcl470 taught by Professor Arnot during the Fall '10 term at University of Toronto- Toronto.

Page1 / 35

Lecture 2b - Spontaneous decomposition of DNA: Oxidation...

This preview shows document pages 1 - 6. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online