- Benzopyrene
Chembox new
Name = Benzopyrene
ImageFile = Benzo-a-pyrene.svg
ImageSize = 180px
ImageName = Benzopyrene
IUPACName = Benzo [a] pyrene
Section1 = Chembox Identifiers
CASNo=50-32-8
SMILES = c1cc2cc/cc3ccc4cc5ccccc5c1c4c23
Section2 = Chembox Properties
C=20|H=12
Density = 1.24 g/cm³
MeltingPt = 179 °C
BoilingPt = 495 °CBenzo [a] pyrene, C20H12, is a five-ring
polycyclic aromatic hydrocarbon that ismutagen ic and highlycarcinogen ic. It is a crystalline yellow solid. Benzo [a] pyrene is a product of incompletecombustion attemperature s between 300 and 600 °C. Benzo [a] pyrene was determined in 1933 to be the component ofcoal tar responsible for the first recognized occupation-associated cancers, the sooty warts (cancers of thescrotum ) suffered bychimney 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, the toxicity of benzo [a] pyrene was demonstrated when malignant skin tumors were produced in laboratory animals by repeatedly painting them with coal tar.ources of Benzo [a] pyrene
Benzo [a] pyrene is found in
coal tar , in automobile exhaust fumes (especially fromdiesel engines),tobacco smoke ,marijuana smoke,incense smoke,wood smoke , and incharbroil ed food. Recent studies have revealed that levels of benzo [a] pyrene in burnttoast are significantly higher than once thought,fact|date=June 2008 although it is unproven whether burnt toast is itself carcinogenic.Toxicity of Benzo [a] pyrene
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 betweenvitamin A andemphysema insmokers . [cite web | title=Benzopyrene and Vitamin A deficiency | work=Researcher links cigarettes, vitamin A and emphysema | url=http://www.tobacco.org/news/171229.html| accessmonthday=March 5 | accessyear=2005] 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 tolung cancer . [ 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.] Benzo [a] pyrene, found in tobacco smoke, was shown to cause genetic damage in lung cells that was identical to the damage observed in theDNA of most malignantlung 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 thebarbecue , particularlysteak s,chicken with skin, andhamburger s. Fact|date=February 2007Japan ese scientists showed that cookedbeef contains mutagens, chemicals that are capable of altering the chemical structure ofDNA Fact|date=February 2007. However, the foods themselves are not necessarily carcinogenic, even if they contain trace amounts of carcinogens, because the gastrointestinal tract protects itself againstcarcinoma s 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)CYP1A1 andCYP1B1 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. UnlessCYP1B1 is also knocked out, benzo [a] pyrene toxicity results from thebioactivation of benzo [a] pyrene to the ultimate toxic compound, benzo [a] pyrene-7,8-dihydrodiol-9,10-epoxide (see below). [Data presented by Daniel W. Nebert in research seminars 2007]Interaction with DNA
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 nucleophilicguanine nucleobase s at the N2 position. X-ray crystallographic andnuclear magnetic resonance structure studies show that this binding distorts the DNA, [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.] inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence ofcancer after exposure. This mechanism of action is similar to that ofaflatoxin which binds to the N7 position of guanine. [Eaton DL, Gallagher EP. Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol. 1994;34:135-72.]There are indications that benzo [a] pyrene diol epoxide specifically targets the protective
p53 gene. [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.] This gene is atranscription factor that regulates thecell cycle and hence functions as atumor suppressor . By inducing G (guanine ) to T (thymidine )transversion s in transversion hotspots withinp53 , there is a probability that benzo [a] pyrene diol epoxide inactivates 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 epoxide. [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] :(2) This product is metabolized by
epoxide hydrolase , opening up theepoxide ring to yield (-)benzo [a] pyrene 7,8,dihydrodiol.:(3)The ultimatecarcinogen 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. [Whitlock JP Jr. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol. 1999;39:103-25.] Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator ) and then bindsxenobiotic 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. [Whitlock JP Jr. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol. 1999;39:103-25.] This process is similar to induction of CYP1A1 by certainpolychlorinated biphenyl s anddioxin s.Recently, Benzo [a] pyrene has been found to activate a transposon, LINE1, in humans. [Vilius Stribinskis and Kenneth S. Ramos (2006). Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, a Ubiquitous Environmental Carcinogen. Cancer Res 2006; 66: (5).]
References
*cite web | title=Lung cancer as consequence by Benzopyrene in
smoke rs | work=Lung Cancer| url=http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html| accessmonthday=March 5 | accessyear=2005
*cite web | title=Levels of Benzopyrene in Burnt toasts| work=Guardian Unlimited | Special reports | Close encounters| url=http://www.guardian.co.uk/chemicalworld/story/0,14534,1219603,00.html | accessmonthday=March 5 | accessyear=2005
*cite web | title=DNA interaction with Benzopyrene| work=DNA| url=http://www.mybiology.com/chime/dna_benzopyrene/dna_benzopyrene_text.htm| accessmonthday=March 5 | accessyear=2005
*cite web | title=Crystal and molecular structure of a benzo-a-pyrene 7,8-diol 9,10-epoxide N2-deoxyguanosine adduct: Absolute configuration and conformation | work=Proceedings of the National Academy of Sciences| url=http://www.pnas.org/cgi/content/full/101/6/1433 |accessmonthday=January 3 |accessyear=2006See also
*
Cigarette
*Barbecue
*Benzene
*Pyrene , a four-ring analogue
*Toxification External links
*ICSC|0104|01
* [http://www.npi.gov.au/database/substance-info/profiles/74.html National Pollutant Inventory - Polycyclic Aromatic Hydrocarbon Fact Sheet]
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