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Benzopyrene

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Benzopyrene

Chemical name	Benzo[a]pyrene
Chemical formula	C₂₀H₁₂
Molecular mass	252.31 g/mol
CAS number	[50-32-8]
Density	1.24 g/cm³
Melting point	179 °C
Boiling point	495 °C
SMILES	c1\cc2\cc/cc3ccc4cc5ccccc5c1c4c23
Disclaimer and references

Benzo[a]pyrene, C₂₀H₁₂, is a five-ring polycyclic aromatic hydrocarbon that is mutagenic and highly carcinogenic. It is a crystalline yellow solid. Benzo[a]pyrene is a product of incomplete combustion at temperatures between 300 and 600 °C. Benzo[a]pyrene 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.

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[edit] Sources of Benzo[a]pyrene

Benzo[a]pyrene 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 benzo[a]pyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic.

[edit] Toxicity of Benzo[a]pyrene

Chemical structure of the carcinogen benzopyrene diol epoxide

A vast number of studies over the previous three decades have documented links between benzo[a]pyrene and cancers. It has been more difficult to link cancers to specific benzo[a]pyrene 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.^[1] Benzo[a]pyrene 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.^[2] Benzo[a]pyrene, 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 benzo[a]pyrene to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers. ^{[citation needed]} Japanese scientists showed that cooked beef contains mutagens, chemicals that are capable of altering the chemical structure of DNA ^{[citation needed]}. 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 benzo[a]pyrene 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 benzo[a]pyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of benzo[a]pyrene, and that removing this protection causes the biological accumulation of large concentrations of benzo[a]pyrene. Unless CYP1B1 is also knocked out, benzo[a]pyrene toxicity results from the bioactivation of benzo[a]pyrene to the ultimate toxic compound, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (see below).^[3]

[edit] Interaction with DNA

Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA.^[4]

Properly speaking, benzo[a]pyrene is a procarcinogen, meaning that the mechanism of carcinogensis of benzo[a]pyrene depends on enzymatic metabolism of benzo[a]pyrene to the ultimate mutagen, benzo[a]pyrene 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,^[5] inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, and can lead to cancer. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.^[6]

Benzo[a]pyrene diolepoxide may increase mutations specifically in the protective p53 gene.^[7] 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, benzo[a]pyrene diolepoxide may inactivate the tumor suppression ability in certain cells, leading to cancer.

Benzo[a]pyrene diol epoxide is the carcinogenic product of three enzymatic reactions:

(1) Benzo[a]pyrene is first oxidized by cytochrome P4501A1 to form a variety of products, including (+)-benzo[a]pyrene 7,8-oxide.^[8]

(2) This product is metabolized by epoxide hydrolase, opening up the epoxide ring to yield (-)-benzo[a]pyrene-7,8,dihydrodiol.

(3)The ultimate carcinogen is formed after another reaction with cytochrome P4501A1 to yield the benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.

Benzo[a]pyrene induces cytochrome P4501A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol.^[9] 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.^[10] This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins.

Recently, Benzo[a]pyrene has been found to activate a transposon, LINE1, in humans^[11]

[edit] References

Lung cancer as consecuence by Benzopyrene in smokers. Lung Cancer. Retrieved on March 5, 2005.
Levels of Benzopyrene in Burnt toasts. Guardian Unlimited. Retrieved on March 5, 2005.
DNA interaction with Benzopyrene. DNA. Retrieved on March 5, 2005.
Crystal and molecular structure of a benzo-a-pyrene 7,8-diol 9,10-epoxide N2-deoxyguanosine adduct: Absolute configuration and conformation. Proceedings of the National Academy of Sciences. Retrieved on January 3, 2006.

^ Benzopyrene and Vitamin A deficiency. Researcher links cigarettes, vitamin A and emphysema. Retrieved on March 5, 2005.
^ Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996 October 18;274(5286):430-2.
^ Data presented by Daniel W. Nebert in research seminars 2007
^ Created from PDB 1JDG
^ Volk DE, Thiviyanathan V, Rice JS, Luxon BA, Shah JH, Yagi H, Sayer JM, Yeh HJ, Jerina DM, Gorenstein DG. Solution structure of a cis-opened (10R)-N6-deoxyadenosine adduct of (9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in a DNA duplex. Biochemistry. 2003 February 18;42(6):1410-20.
^ Eaton DL, Gallagher EP. Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol. 1994;34:135-72.
^ Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002 October 21;21(48):7435-51.
^ Shou M, Gonzalez FJ, Gelboin HV. Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase.Biochemistry. 1996 December 10;35(49):15807-13
^ Whitlock JP Jr. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol. 1999;39:103-25.
^ Whitlock JP Jr. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol. 1999;39:103-25.
^ Vilius Stribinskis and Kenneth S. Ramos (2006). Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen. Cancer Res 2006; 66: (5).