Toxicology of Tobacco I

Now we're moving onto the respiratory system in PHAR3303! (And what good timing too, considering that we're learning about the respiratory system in PHYL3002 as well :P)

Demonstrate understanding of the main steps in the manufacturing of cigarettes together with an appreciation of the toxicological implications of some processing steps.

It can take months to prepare tobacco. In the first step, the leaves are dried through a process known as "curing." This preserves the leaf by decreasing its water content. Curing also destroys the chlorophyll, hence turning tobacco yellow. Other processes then take place, such as partial rehydration and removal of the stems. Additives can also be added to the tobacco in order to improve its flavour or aroma later on. Once the leaves are ready, they are chopped up, blended and then packaged into cigarettes.

Crop production may introduce some contaminants into the cigarette. Aside from pesticides, herbicides and so on used when growing the plant, tobacco can also become contaminated by microbes.

Now let's talk about the cigarette itself! The cigarette paper may have been treated with whitening agents, inks, adhesives and so on, which can add even more contaminants to the smoke. There are also other features of the cigarette that can affect how much stuff actually gets to the smoker's lungs. The rolling paper can affect the air flow and yield, the filter can prevent some (but not all!) of contaminants from getting to the smoker's lungs, and vents can help to dilute the smoke. Of course, this is all far from perfect, as there are still many tobacco-related deaths every year.

Show an understanding of the two common ways of thinking about the different types of smoke released from a burning cigarette.

There are two main ways of thinking about the different types of smoke.

In the first classification system, smoke can be classified as mainstream, sidestream or environmental. Mainstream smoke is the stuff that gets inhaled, sidestream smoke is the smoke that comes off the end of the cigarette, and environmental smoke is a mixture of sidestream smoke and the mainstream smoke exhaled when the smoker breathes out.

In the second classification system, smoke can be classified as first-hand, second-hand or third-hand. First-hand smoke is analogous to mainstream smoke, whereas second-hand smoke is analogous to environmental smoke. Third-hand smoke refers to the smoke residue that gets deposited on surfaces.

Identify 3 major carcinogen classes in tobacco smoke, showing awareness of any role of metabolism in converting such species to genotoxic or DNA adduct-forming metabolites.

This lecture covered three main toxic compounds: nitrosamines, 1,3-butadiene (BD) and acetaldehyde.

Nitrosamines

Nitrosamines are bioactivation-dependent: that is, they need to be metabolised before they can start causing damage. Nicotine can undergo a process called N-nitrosation which can form NNN and NNK. NNN and NNK are potent carcinogens as they can attack DNA and form methylated bases. (These altered bases are also known as "DNA adducts.") These methylated bases can then cause incorrect base pairs to form. For example, guanine can be methylated to form O⁶-Me-G (the "Me" stands for "methyl"), which pairs with thymine rather than cytosine.

1,3-butadiene (BD)

1,3-butadiene is quite important, partially due to its high prevalence in tobacco smoke. BD is also present in other things such as in the synthesis of polymers or the exhaust gases from cars. In rodents, it can cause cancer in multiple different organs.

1,3-butadiene, like nicotine, is also bioactivation-dependent. CYP2E1, an isoform of CYP450, catalyses its breakdown into 1,2-epoxy-3-butene, or EB. EB can attack guanine, forming a deoxyinosine adduct which can cause incorrect base pairing and mutations.

Acetaldehyde

Acetaldehyde, which is also prevalent in tobacco smoke, does not require bioactivation to become carcinogenic. It's not 100% confirmed how it causes cancer, but it's possible that DNA adducts play a role. Deoxyguanosine, for example, can form a weakly mutagenic adduct when combined with acetaldehyde, but this adduct can also block DNA replication.

Understand the major biological outcomes of DNA adduct formation, namely DNA repair, apoptosis and mutagenesis.

DNA adducts have three main outcomes. Firstly, DNA repair mechanisms might kick in and fix the damage. Secondly, damage to the DNA may trigger the cell to undergo apoptosis (cell death). Thirdly, DNA adducts may cause incorrect base pairs to form, essentially causing mutations. Depending on the genes that are altered, cancer may result.

Also, it's important to note that not all of the bad stuff in cigarettes cause cancer. Some toxic chemicals are related to other negative outcomes, such as COPD. For example, acrolein is a chemical that might play a role in COPD development due to its reactivity with proteins and DNA.