Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer

Abstract

Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets, such as lipids, proteins, and nucleic acids. A growing body of evidence supports a key role for smoking-induced ROS and the resulting oxidative stress in inflammation and carcinogenesis. This comprehensive and up-to-date review covers four interrelated topics, including 'smoking', 'oxidative stress', 'inflammation', and 'cancer'. The review discusses each of the four topics, while exploring the intersections among the topics by highlighting the macromolecular damage attributable to ROS. Specifically, oxidative damage to macromolecular targets, such as lipid peroxidation, post-translational modification of proteins, and DNA adduction, as well as enzymatic and non-enzymatic antioxidant defense mechanisms, and the multi-faceted repair pathways of oxidized lesions are described. Also discussed are the biological consequences of oxidative damage to macromolecules if they evade the defense mechanisms and/or are not repaired properly or in time. Emphasis is placed on the genetic- and epigenetic alterations that may lead to transcriptional deregulation of functionally-important genes and disruption of regulatory elements. Smoking-associated oxidative stress also activates the inflammatory response pathway, which triggers a cascade of events of which ROS production is an initial yet indispensable step. The release of ROS at the site of damage and inflammation helps combat foreign pathogens and restores the injured tissue, while simultaneously increasing the burden of oxidative stress. This creates a vicious cycle in which smoking-related oxidative stress causes inflammation, which in turn, results in further generation of ROS, and potentially increased oxidative damage to macromolecular targets that may lead to cancer initiation and/or progression.

Keywords: Carcinogenesis; Inflammatory disease; Oxidative damage; Reactive oxygen species (ROS); Tar; Tobacco.

Figure 1.. BER-mediated repair of 8-oxodG.

ROS oxidize guanine residues in DNA leading to formation of 8-oxodG (G*). This damage is removed by OGG1 leaving an apurinic (AP) site, which is recognized by APE1 (encoded by the APEX1 gene in humans) that nicks the DNA at the site of damage. PARP1 then recruits POLB to fill the gap with a correct guanine. The gap is sealed by DNA ligase and the original DNA sequence is conserved. If replication occurs before OGG1 has excised the lesion, 8-oxodG pairs with adenine, which upon replication, results in G:C→T:A mutation. Alternatively, MUTYH excises the mispaired adenine with 8-oxodG, POLB preferentially inserts a cytosine in its place, and the above cycle continues to repeat itself. As discussed in the text, the DNA repair and mutagenic pathways for oxidative damage are highly complex, involving numerous determinants, including various proteins, enzymes, substrates, cofactors, etc. Of these, we have focused on the most prominent determinants that are specifically covered in this review. We note that this figure is a simplified visualization of the highly complex and multi-component reactions occurring during oxidative DNA damage, repair, and mutagenesis, as described in the text. Interested readers are referred to elegant papers, including references [, , , , , , , , and 145], which have discussed other specialized aspects of DNA damage/repair & mutagenesis that are outside the scope of this review. APE1: apurinic/apyrimidinic endodeoxyribonuclease; MUTYH: mutY DNA glycosylase; OGG1: 8-oxoguanine DNA glycosylase; PARP1: poly(ADP-ribose) polymerase 1; POLB: DNA polymerase beta.

Figure 2.. Direct and indirect accumulation of 8-oxodG in DNA and prevention of mutagenesis by NUDT1.

8-oxodG (G*) accumulates in DNA through two distinct pathways, including: (1) direct oxidation of guanine residues; and (2) misincorporation of oxidized guanine nucleosides (8-oxo-7,8-dihydro-2′- deoxyguanosine 5′-triphosphate (8-OHdGTP)), which upon two rounds of replication, result in G:C→T:A and A:T→C:G transversion mutations, respectively. With a properly functioning NUDT1 (also known as MutT homolog 1 (MTH1)) enzyme, 8-OHdGTP is hydrolyzed to a monophosphate form (8-oxo-dGMP) plus pyrophosphate (PPi), which can no longer be incorporated into the DNA, thus preventing mutagenesis. We note that this figure is a simplified visualization of the highly complex and multi-component reactions occurring during oxidative DNA damage, repair, and mutagenesis, as described in the text. Interested readers are referred to elegant papers, including references [, , , , , , , , and 145], which have discussed other specialized aspects of DNA damage/repair & mutagenesis that are outside the scope of this review. NUDT1: nudix hydrolase 1 also known as MTH1.

Figure 3.. The cycle of smoking-induced oxidative damage and inflammation.

A simplified schematic diagram of the feedback loop between smoking-induced oxidative stress and the inflammatory response is shown (see, text for detailed description).