Toxicology of Tobacco II

In my last post, I wrote about the carcinogenic compounds in cigarettes. In this post, I'll be talking about free radicals.

Demonstrate basic understanding of the main chemical species formed during oxidative stress

Firstly, I should give a quick definition of oxidative stress. Oxidative stress occurs when there are more free radicals produced than removed. (Free radicals can be removed by antioxidants.)

The main species formed from oxidative stress can be classified into two main categories: reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS include superoxide, hydrogen peroxide and hydroxyl radicals. RNS includes NO radicals and ONO₂CO₂^-, which I know virtually nothing abut other than that it can be very damaging.

Show an understanding of how redox-cycling quinones are a source of superoxide radicals in tobacco smoke-exposed lungs.

Redox-cycling quinones in tar can produce free radicals, such as superoxide. Some quinone-containing compounds, such as the hydroquinone-quinine complex, are formed during the incomplete combustion of tobacco leaves.

Identify major products of oxidative damage to proteins and unsaturated fatty acids, and their use as biomarkers.

8-isoprostane is a common product of oxidative damage. It is formed by free radical attack on arachidonic acid. Carbonyl-adducted proteins (i.e. proteins with carbonyl attached) are also common products of oxidative damage. These products can also be used as biomarkers, i.e. their concentrations can be measured to determine the extent of oxidative stress,

Show how smoke-derived ROS may cause 2 pathological features of COPD: elastase activation and proinflammatory gene expression secondary to chromatin remodelling.

Elastase Activation

Human neutrophil elastase (HNE) mediates degradation of elastin fibres in alveolar walls, leading to emphysema. Usually, HNE is inhibited by α₁-antitrypsin, but when α₁-antitrypsin is oxidised due to ROS, it can no longer bind to and inhibit elastase.

Gene Expression

ROS may regulate kinases that affect the acetylation, methylation and so on of histones (proteins that the DNA are wound around). This can affect cell signalling and gene expression. For example, ROS can deplete SIRT1, which is a deacetylase that normally represses chronic inflammation, sensecence (cell aging) and apoptosis. When SIRT1 is depleted, it can no longer repress these processes, so cell aging, death and so forth become more prevalent.