Benzopyrene

# Overview
Benzopyrene, C20H12,  is a five-ring polycyclic aromatic hydrocarbon that is mutagenic and highly carcinogenic. It is a crystalline yellow solid. Benzopyrene is a product of incomplete combustion at temperatures between 300 and 600 C. Benzopyrene was determined in 1933 to be the component of coal tar responsible for the first recognized occupation-associated cancers, the sooty warts (cancers of the scrotum) suffered by chimney sweeps in 18th century England. In the 19th century, high incidences of skin cancers were noted among fuel industry workers. By the early 20th century, malignant skin tumors were produced in laboratory animals by repeatedly painting them with coal tar.

# Sources of Benzopyrene
Benzopyrene is found in coal tar, in automobile exhaust fumes (especially from diesel engines), tobacco smoke, wood smoke, and in charbroiled food. Recent studies have revealed that levels of benzopyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic.

# Toxicity of Benzopyrene
A vast number of studies over the previous three decades have documented links between benzopyrene and cancers.  It has been more difficult to link cancers to specific benzopyrene sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion). Researchers at Kansas State University recently discovered a link between vitamin A and emphysema in smokers. Benzopyrene was found to be the link to the deficiency, since it induces vitamin A deficiency in rats.
In 1996, a study was published that provided the clear molecular evidence conclusively linking components in tobacco smoke to lung cancer. Benzopyrene, found in tobacco smoke, was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours.
A 2001 National Cancer Institute study found levels of benzopyrene to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers. Japanese scientists showed that cooked beef contains mutagens, chemicals that are capable of altering the chemical structure of DNA. However, the foods themselves are not necessarily carcinogenic, even if they contain trace amounts of carcinogens, because the gastrointestinal tract protects itself against carcinomas by shedding its outer layer continuously. Furthermore, detoxification enzymes, such as cytochromes P450 have increased activities in the gut due to the normal requirement for protection from food-borne toxins. Thus in most cases small amounts of benzopyrene are metabolized by gut enzymes prior to being passed on to the blood. The lungs are not protected in either of these manners.
A recent study has found that cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are both protective and, confusingly, necessary for benzopyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of benzopyrene, and that removing this protection causes the biological accumulation of large concentrations of  benzopyrene. Unless CYP1B1 is also knocked out, benzopyrene toxicity results from the bioactivation of benzopyrene to the ultimate toxic compound, benzopyrene-7,8-dihydrodiol-9,10-epoxide (see below).

# Interaction with DNA
Properly speaking, benzopyrene is a procarcinogen, meaning that the mechanism of carcinogensis of benzopyrene depends on enzymatic metabolism of benzopyrene to the ultimate mutagen, benzopyrene diol epoxide, pictured at right. This molecule intercalates in DNA, covalently bonding to the nucleophilic guanine nucleobases at the N2 position.  X-ray crystallographic and nuclear magnetic resonance structure studies show that this binding distorts the DNA, inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of cancer after exposure. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.
There are indications that specifically benzopyrene diol epoxide specifically targets the protective p53 gene. This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. By inducing G (guanine) to T (thymidine) transversions in transversion hotspots within p53, there is a probability that benzopyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.
Benzopyrene diol epoxide is the carcinogenic product of three enzymatic reactions:
Benzopyrene induces cytochrome P4501A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol. Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) and then binds xenobiotic response elements (XREs) in DNA located upstream of certain genes. This process increases transcription of certain genes, notably CYP1A1, followed by increased CYP1A1 protein production. This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins.
Recently, Benzopyrene has been found to activate a transposon, LINE1, in humans