Hi guys! I feel like every science major in history has at some point heard or talked about benzene. And the common facts are easy; six membered ring, strange stability. Last week in O-Chem we went a bit deeper into what makes benzene tick and what gives it that strange stability. At one point during class, Dr. Carrasco mentioned that benzene was a carcinogen, another pretty common fact. However, when asked what made benzene a carcinogen, Dr. Carrasco answered with "I really don't know exactly why it is a carcinogen."At that point, my mind screamed out, BLOG POST!
So here's a bit more background on benzene. Benzene is an organic compound with molecular formula C6H6. It is a six-membered ring with alternating carbon double bonds with all the same length. The common name is benzene, but the systematic name is cyclohexa- 1,3,5-triene. It is classified as an aromatic hydrocarbon with continuous pi bonds that work in a type of circuit. It is a colorless liquid that is highly flammable but has a sweet smell. Benzene is commonly used as a precursor to mass produced heavy chemicals. Also, due to its high octane levels, it is an important component of gasoline. In the early years after the discovery of benzene and its carcinogenic frequencies it was used for many common things and chores. For example, it was sued as after shave lotion in the early 20th century because of its sweet smell. In the early 1900's it was used to decaffeinate coffee. Historically it has also been used in paint strippers, rubber cement, stain removers, etc.
So, that is all well and good, but there was no mention of what exactly makes benzene a carcinogen. I had to dig a bit deeper and ended up finding an article from the EPA titled, Carcinogenic Effects of Benzene: An Update. While the article is a bit on the older side (1998), I found that it contained a lot of valuable information.
Benzene has commonly been known to primarily cause leukemia, and other blood related disorders. At the time of the study, the mechanism by which exposure to benzene caused cancer was unknown. These days, it is known that benzene and other aromatic hydrocarbons and polycyclic aromatic hydrocarbons are considered ultimate carcinogens because they are able to directly attack DNA bases and form covalent adducts. DNA adducts are known as the new molecular structures that are formed after the covalent linkage of a mutagen with one or another portion of a DNA molecule (Weinberg). The covalent bonding of these mutagens can then lead to oncogenic mutations in DNA. This same effect can be seen from the major benzene metabolites- phenol, catechol, hydroquinone, etc.
The metabolic pathways of benzene were elusive to the scientists performing the study in 1998, and they still, to a point remain somewhat elusive today. Two pathways are hypothesized as responsible for benzene toxicity. The first involves the metabolites of benzene (phenol, etc) and the second involves the open ring formation of benzene. The figure below summarizes these pathways.
As can be seen, the primary metabolizing agent is Cytochrom P450 2E1, which metabolizes benzene to phenol. This conversion is one of the important primary events in benzene toxicity. From there, the two metabolic pathways mentioned above can take place. Phenol can then be metabolized to catechol and hydroquinone which have shown to have higly carcinogenic tendencies. For example, these two benzene metabolites have been known to remain in bone marrow after benzene exposure. These metabolites can then be activated by the peroxidase found in bone marrow which can then lead to DNA damage.
The ring opening pathway, which can be seen at the top of the figure, shows muconic acid as a product and it is relatively un-harmful. The precursor to muconic acid, trans, trans-muconaldehyde however, is known to be one of the most toxic species that can be obtained through benzene metabolism. The problem with trans, trans-muconaldehyde is that it is difficult to isolate and difficult to detect in vivo.
The article goes on to discuss animal trials and mutagenicity and genotoxicity, but that would make this post way too long and frankly a bit dull. Chromosomal rearrangements and losses are cited as a possible cause of its carciogenicity, as well as the formation of DNA adducts as mentioned above.
I liked this article or summary because it was very well written, well organized, and in my opinion well informed. My problem was with finding information for more recent years. I did find some articles, but they were not the most informative and they did not mention directly the metabolic pathway of benzene as was mentioned here.
Another thought that occurred to me was that benzene testing is probably not very popular right now. First off, the reactions and mechanisms of benzene are not very well known. Even in o-chem, the mechanisms for some of the benzene reactions are just questionmarks. This being the case, I can see why some would be reluctant to work with a compound that is not well known but that is known to cause cancer. Also, finding a human testing group that would voluntarily expose themselves to a carcinogen seems to be wishful thinking. Furthermore, since the regulation of benzene in most of the common products that it had been included in, it has become even harder to analyze continued exposure in patients.
I feel a little on the edge with the seemingly lack of benzene research going on. This doesn't mean I want to go out and poison a bunch of people with benzene and its derivatives, but I find benzene interesting and I would hope that some more of the reaction mechanisms and pathways could be discovered and examined. Who knows, maybe that could lead to a definite reason as to why benzene is a carcinogen.
P.S.- Benzene levels are regulated informally in most soft drinks. Benzene levels in common soft drinks result from the decarboxylation of benzoic acid, which is used as a preservative, in the presence of ascorbic acid (vitamin c). This process is heightened of under heat and light. It might make you think twice before indulging in that sugar-filled, carcinogenic soft drink.
References
http://en.wikipedia.org/wiki/Benzene
http://en.wikipedia.org/wiki/Benzene_in_soft_drinks
