Embedded Files
We touched on PAHs in the last page, but let's explore this topic a little more now
First, Let's Try To Understand What a PAH Is
Polycyclic aromatic hydrocarbons (PAHs) are chemicals that are produced when material such as coal, oil, gas and tobacco are burnt. They are ubiquitous in nature. For the purpose of our discussion, it is key to note that cigarette smoke/tobacco contains many PAHs. To further discuss the exposure to PAH, lets read some more.
How Are People Exposed to PAHs?
In the modern world, people are constantly under the exposure to mixtures of PAHs. Polluted air is contaminated with motor vehicle exhausts, cigarette smoke, smoke from burning objects, et cetra. Interestingly, we can also be exposed to PAHs by consuming grilled smokey meat.
Why PAHs Are Bad For You?
Generally, low levels of PAHs have not shown significant health risks. However, it should be noted that we currently do not know the extent of the damage(s) caused by exposure to PAH. Individuals who have been exposed to large amounts of PAHs have been recorded to develop blood and liver abnormalities. For our discussion, we are going to focus on the cancer causing properties of PAHs. You can recall that frameshift mutations and transversions often leads to the production of defective proteins in the p53 pathway that cause the pathway to become ineffective. PAHs are chemicals that enhance the frequency of transversions, increasing the risk of cancer.
The PAH BPDE
Benzopyrene-7,8-diol-9,10-epoxide (BPDE) is a PAH mutagen that covalently binds to DNA. BPDE has been identified as a potent inducer of frameshift mutations and base substations. Research has shown that a majority of mutations induced by BPDE are transversions.
How We Know
Mazur et al selected mutants to study by
creating independent cultures where cells were exposed to aracemic mixture of BPDE. They found:
a) The most common mutation was the G to C -> T to A transversion.
b) Additional findings:
The G:C -> C:G transversion and A:T -> T:A transversions were less frequently recovered. They also found a single transition mutation which was a G:C-> A:T event.
c) The mutational specificity and high concentrations of G to T transversion is likely the consequence of the N2-substituted guanine adduct, which occupies the minor groove of the DNA double helix and possibly interferes with base pairing.
Because the study was done with a large sample size and the cultures were categorized and divided broadly, this study is well conducted and its data can be reasonably considered to be applicable in the real world.
You Should Also Know
Denissenko et al, in an attempt to investigate the relationship between BPDE adducts and p53 mutations, mapped the distribution of BPDE adducts along the p53 gene using Litigation Mediated PCR. Here:
a) Cells were treated with different concentrations of BPDE and the DNA was extracted.
b) They further tested weather the adduct formation was specific to the chromatin structures involved by comparing the p53 gene treated with BPDE from Cells with p53 genes treated with BPDE from the genomic DNA.
c) They found that in both cases, the BPDE adduct formation was near identical.
d) Their research showed that p53 mutation hotspots 157, 248 and 273 are selective BPDE binding sites. The coincidence of mutation hotspots and BPDE binding hotspots suggests that BPDE is involved in mutations leading to lung cancers.
Here, the sample was tested with well developed techniques where similar results (hotspots) will likely be found in virtually any other lab in the world ,given the same conditions are provided. This gives the results of this study a lot of credibility.
Now that we know how BPDE affects DNA, let's also look at how BPDE interacts with the p53 pathway:
In normal circumstances, DNA damage results in the phosphorylation of p53 protein as we have learned before. When p53 is phosphorylated, it is no longer able to interact with MDM2, a negative regulator of p53. This results in the subsequent activation of the p53 pathway that halts the cell cycle for DNA repair or induces cell apoptosis.
In the presence of BPDE, Calcium (Ca2+ in the figure) concentrations rise which results in an increase of Pyk2 activity. Pyk2 then mediates anti-apoptotic AKT signaling.
When we consider the fact that BPDE starts a chain of reactions that ultimately leads to the p53 pathway being blocked as a result of the anti-apoptotic AKT pathway being activated, we see how BPDE plays a role in lung cancer with interacting with the p53 pathway.
You can see the BPDE induced anti apoptotic pathway in the figure below.
Animesh Dali | DePauw University
Page updated
Report abuse