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Benzo(a)pyrene

January 01, 1970

The correct title of this article is Benzo[a]pyrene. The substitution of any brackets is due to technical restrictions.

Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites, more commonly known as BPDE, react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

Benzo[a]pyrene



Names
Preferred IUPAC name
Benzo[pqr]tetraphene[1]
Other names
  • Benz[a]pyrene
  • Benzo[a]pyrene
  • 3,4-Benzpyrene
  • 3,4-Benzopyrene
  • 3,4-Benz[a]pyrene
  • 3,4-Benzo[a]pyrene
  • Pentacyclo[10.6.2.02,7.09,19.016,20]icosa-1,3,5,7,9,11,13,15,17,19-decaene[citation needed]
Identifiers
  • 50-32-8 Y
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:29865 Y
ChEMBL
  • ChEMBL31184 Y
ChemSpider
  • 2246 Y
ECHA InfoCard 100.000.026
EC Number
  • 200-028-5
KEGG
  • C07535 Y
  • 2336
RTECS number
  • DJ3675000
UNII
  • 3417WMA06D
UN number 3077, 3082
  • DTXSID2020139
  • InChI=1S/C20H12/c1-2-7-17-15(4-1)12-16-9-8-13-5-3-6-14-10-11-18(17)20(16)19(13)14/h1-12H Y
    Key: FMMWHPNWAFZXNH-UHFFFAOYSA-N Y
  • InChI=1/C20H12/c1-2-7-17-15(4-1)12-16-9-8-13-5-3-6-14-10-11-18(17)20(16)19(13)14/h1-12H
    Key: FMMWHPNWAFZXNH-UHFFFAOYAQ
  • c1ccc2c(c1)cc3ccc4cccc5c4c3c2cc5
Properties
C20H12
Molar mass 252.316 g·mol−1
Density 1.24 g/cm3 (25 °C)
Melting point 179[2] °C (354 °F; 452 K)
Boiling point 495 °C (923 °F; 768 K)
0.2 to 6.2 μg/L
-135.7·10−6 cm3/mol
Hazards[3]
GHS labelling:
Danger
H317, H340, H350, H360, H410
P201, P202, P261, P272, P273, P280, P281, P302+P352, P308+P313, P321, P333+P313, P363, P391, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)

Description edit

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon found in coal tar with the formula C20H12. The compound is one of the benzopyrenes, formed by a benzene ring fused to pyrene, and is the result of incomplete combustion at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F).

Sources edit

The main source of atmospheric BaP is residential wood burning.[4] It is also found in coal tar, in automobile exhaust fumes (especially from diesel engines), in all smoke resulting from the combustion of organic material (including cigarette smoke), and in charbroiled food. A 2001 National Cancer Institute study found levels of BaP to be significantly higher in foods that were cooked well-done on the barbecue, particularly steaks, chicken with skin, and hamburgers: Cooked meat products have been shown to contain up to 4 ng/g of BaP,[5] and up to 5.5 ng/g in fried chicken[6] and 62.6 ng/g in overcooked charcoal barbecued beef.[7]

BaP is discharged in wastewater by industries such as smelters, particularly iron and steel mills[8] and aluminium smelters.[9]

History edit

In the 18th century, young British chimney sweeps who climbed into chimneys suffered from chimney sweeps' carcinoma, a scrotal cancer peculiar to their profession, and this was connected to the effects of soot in 1775,[10] in the first work of occupational cancer epidemiology and also the first connection of any chemical mixture to cancer formation. Frequent skin cancers were noted among fuel industry workers in the 19th century. In 1933, BaP was determined to be the compound responsible for these cases, and its carcinogenicity was demonstrated when skin tumors occurred in laboratory animals repeatedly painted with coal tar.[11] BaP has since been identified as a prime carcinogen in cigarette smoke.[12]

Toxicity edit

 
Benzo[a]pyrene, showing the base pyrene ring and numbering and ring fusion locations according to IUPAC nomenclature of organic chemistry.

Nervous system edit

Prenatal exposure of BaP in rats is known to affect learning and memory in rodent models. Pregnant rats eating BaP were shown to negatively affect the brain function in the late life of their offspring. At a time when synapses are first formed and adjusted in strength by activity, BaP diminished NMDA receptor-dependent nerve cell activity measured as mRNA expression of the NMDA NR2B receptor subunit.[13]

Immune system edit

BaP has an effect on the number of white blood cells, inhibiting some of them from differentiating into macrophages, the body's first line of defense to fight infections. In 2016, the molecular mechanism was uncovered as damage to the macrophage membrane's lipid raft integrity by decreasing membrane cholesterol at 25%. This means less immunoreceptors CD32 (a member of the Fc family of immunoreceptors) could bind to IgG and turn the white blood cell into a macrophage. Therefore, macrophage membranes become susceptible to bacterial infections.[14]

Reproductive system edit

In experiments with male rats, subchronic exposure to inhaled BaP has been shown to generally reduce the function of testicles and epididymis with lower sex steroid/testosterone production and sperm production.[15]

Carcinogenicity edit

BaP's metabolites are mutagenic and highly carcinogenic, and it is listed as a Group 1 carcinogen by the IARC. Chemical agents and related occupations, Volume 10, A review of Human Carcinogens, IARC Monographs, Lyon France 2009 [16]

In June 2016, BaP was added as benzo[def]chrysene to the REACH Candidate List of Substances of very high concern for Authorisation.[17]

Numerous studies since the 1970s have documented links between BaP and cancers.[18] It has been more difficult to link cancers to specific BaP sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion).[19] A link between vitamin A deficiency and emphysema in smokers was described in 2005 to be due to BaP, which induces vitamin A deficiency in rats.[20]

A 1996 study provided molecular evidence linking components in tobacco smoke to lung cancer. BaP was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours.[21]

Regular consumption of cooked meats has been epidemiologically associated with increased levels of colon cancer[22] (although this in itself does not prove carcinogenicity),[23] A 2005 NCI study found an increased risk of colorectal adenomas was associated with BaP intake, and more strongly with BaP intake from all foods.[24]

The detoxification enzymes cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are both protective and necessary for benzo[a]pyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1 and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of BaP, and that removing this protection accumulates large concentrations of BaP. Unless CYP1B1 is also knocked out, toxicity results from the bioactivation of BaP to benzo[a]pyrene -7,8-dihydrodiol-9,10-epoxide, the ultimate toxic compound.[25][better source needed]

Interaction with DNA edit

 
Metabolism of benzo[a]pyrene yielding the carcinogenic benzo[a]pyren-7,8-dihydrodiol-9,10-epoxide.
 
A DNA adduct (at center) of benzo[a]pyrene, the major mutagen in tobacco smoke.[26]

Properly speaking, BaP is a procarcinogen, meaning that its mechanism of carcinogenesis depends on its enzymatic metabolism to BaP diol epoxide[27] It intercalates in DNA, and the electrophilic epoxide is attacked by nucleophilic guanine bases, forming a bulky guanine adduct.[27]  

X-ray crystallographic and nuclear magnetic resonance structure studies have shown how this binding distorts the DNA[28] by confusing the double-helical DNA structure. This disrupts the normal process of copying DNA and causes 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.[29]

There are indications that benzo[a]pyrene diol epoxide specifically targets the protective p53 gene.[30] 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 benzo[a]pyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.

Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is the carcinogenic product of three enzymatic reactions:[31]

  1. Benzo[a]pyrene is first oxidized by cytochrome P450 1A1 to form a variety of products, including (+)benzo[a]pyrene-7,8-epoxide.[32]
  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 P450 1A1 to yield the (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.

BaP induces cytochrome P450 1A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol.[33] 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.[33] This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo[a]pyrene to enter portal blood and systemic circulation.[34] Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2),[35] which is a eukaryotic receptor for bacterial surface structures such as lipoteichoic acid.

Moreover, BaP has been found to activate a transposon, LINE1, in humans.[36]

Nucleotide excision repair edit

As illustrated above, (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) forms bulky covalent DNA adducts with guanines. Most of these adducts can be efficiently eliminated from DNA by the process of nucleotide excision repair.[37] Those adducts that are not removed can cause errors during DNA replication leading to carcinogenic mutations.

See also edit

References edit

  1. ^ Henri A. Favre, Warren H. Powell (2013). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. Royal Society of Chemistry. p. 232. ISBN 978-0-85404-182-4.
  2. ^ William M. Haynes (2016). CRC Handbook of Chemistry and Physics (97th ed.). Boca Raton: CRC Press. pp. 3–42. ISBN 978-1-4987-5429-3.
  3. ^ "benzo[a]pyrene". pubchem.ncbi.nlm.nih.gov.
  4. ^ "Assessment of Benzo-alpha-pyrene Emissions in the Great Lakes Region" (PDF). pp. 23–24.
  5. ^ Kazerouni, N; Sinha, R; Hsu, CH; et al. (2002). "Analysis of 200 food items for benzo[a]pyrene and estimation of its intake in an epidemiologic study". Food and Chemical Toxicology. 40 (1): 423–36. doi:10.1016/S0278-6915(00)00158-7. PMID 11313108.
  6. ^ Lee, BM; Shim, GA (Aug 2007). "Dietary exposure estimation of benzo[a]pyrene and cancer risk assessment". Journal of Toxicology and Environmental Health Part A. 70 (15–16): 1391–4. doi:10.1080/15287390701434182. PMID 17654259. S2CID 21302834.
  7. ^ Aygün, SF; Kabadayi, F (December 2005). "Determination of benzo[a]pyrene in charcoal grilled meat samples by HPLC with fluorescence detection". Int J Food Sci Nutr. 56 (8): 581–5. doi:10.1080/09637480500465436. PMID 16638662. S2CID 35095622.
  8. ^ U.S. Environmental Protection Agency (EPA), Washington, D.C. (2002). "Iron and Steel Manufacturing Point Source Category." Code of Federal Regulations, 40 CFR Part 420.
  9. ^ EPA (1984). "Nonferrous Metals Manufacturing Point Source Category." Code of Federal Regulations, 40 CFR Part 421.
  10. ^ Pott, Percivall (1775). Chirurgical Observations …. London, England: L. Hawes, W. Clarke, and R. Collins. pp. 63–68. From p. 67: "The disease, in these people [i.e., chimney sweeps], seems to derive its origin from a lodgment of soot in the rugae of the scrotum, … "
  11. ^ Cook, J. W.; Hewett, C. L.; Hieger, I. (1933). "The isolation of a cancer producing Hydrocarbon from coal tar". J. Chem. Soc. 1933: 395–405. doi:10.1039/jr9330000395.
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  14. ^ Clark RS, Pellom ST, Booker B, et al. (2016). "Validation of research trajectory 1 of an Exposome framework: Exposure to benzo[a]pyrene confers enhanced susceptibility to bacterial infection". Environ Research. 146: 173–84. Bibcode:2016ER....146..173C. doi:10.1016/j.envres.2015.12.027. PMC 5523512. PMID 26765097.
  15. ^ Ramesh A1, Inyang F; Lunstra, DD; Niaz, MS; et al. (Aug 2008). "Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene". Exp Toxicol Pathol. 60 (4–5): 269–80. doi:10.1016/j.etp.2008.02.010. PMC 3526104. PMID 18499416.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  16. ^ A review of human carcinogens—part F: chemical agents and related occupations
  17. ^ European Chemicals Agency. "ED/21/2016". ECHA. Retrieved 21 June 2016.
  18. ^ Kleiböhmer, W. (2001). "Polycyclic Aromatic Hydrocarbon (PAH) Metabolites". Environmental Analysis (Volume 3 of Handbook of Analytical Separations). Elsevier. pp. 99–122. ISBN 978-0-08-050576-3.
  19. ^ Armstrong, B.; Hutchinson, E.; Unwin, J.; Fletcher, T. (2004). "Lung Cancer Risk After Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis". Environmental Health Perspectives. 112 (9): 970–978. doi:10.1289/ehp.6895. PMC 1247189. PMID 15198916.
  20. ^ "Benzopyrene and Vitamin A deficiency". Researcher links cigarettes, vitamin A and emphysema. Retrieved March 5, 2005.
  21. ^ Denissenko, M. F.; Pao, A.; Tang, M.; Pfeifer, G. P. (1996-10-18). "Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53". Science. 274 (5286): 430–432. Bibcode:1996Sci...274..430D. doi:10.1126/science.274.5286.430. PMID 8832894. S2CID 3589066.
  22. ^ Le Marchand, L; Hankin, JH; Pierce, LM; et al. (September 2002). "Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii". Mutat. Res. 506–507: 205–14. doi:10.1016/s0027-5107(02)00167-7. PMID 12351160.
  23. ^ Truswell, AS (Mar 2002). "Meat consumption and cancer of the large bowel". European Journal of Clinical Nutrition. 56 (Suppl 1): S19–24. doi:10.1038/sj.ejcn.1601349. PMID 11965518. S2CID 23886438.
  24. ^ Sinha, Rashmi; Kulldorff, Martin; Gunter, Marc J.; et al. (August 2005). "Dietary benzo[a]pyrene intake and risk of colorectal adenoma". Cancer Epidemiology, Biomarkers & Prevention. 14 (8): 2030–2034. doi:10.1158/1055-9965.EPI-04-0854. PMID 16103456. S2CID 33819830.
  25. ^ Data presented by Daniel W. Nebert in research seminars 2007
  26. ^ Created from PDB 1JDG 2008-09-22 at the Wayback Machine
  27. ^ a b Bogdan, Dennis Paul (February 1, 1973). Interactions Of Benzopyrene And Nucleic Acids In The Presence Of A Mixed-Function Oxidase System - Ph.D. Dissertation (requires login). ISBN 979-8661021359. ProQuest 302781013. Retrieved May 9, 2021. {{cite book}}: |work= ignored (help)
  28. ^ Volk, David E.; Thiviyanathan, Varatharasa; Rice, Jeffrey S.; et al. (2003-02-18). "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. 42 (6): 1410–1420. doi:10.1021/bi026745u. PMID 12578353.
  29. ^ Eaton, D. L.; Gallagher, E. P. (1994). "Mechanisms of aflatoxin carcinogenesis". Annual Review of Pharmacology and Toxicology. 34: 135–172. doi:10.1146/annurev.pa.34.040194.001031. PMID 8042848.
  30. ^ Pfeifer, Gerd P.; Denissenko, Mikhail F.; Olivier, Magali; et al. (2002-10-21). "Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers". Oncogene. 21 (48): 7435–7451. doi:10.1038/sj.onc.1205803. PMID 12379884. S2CID 6134471.
  31. ^ Jiang, Hao; Gelhaus, Stacy L.; Mangal, Dipti; et al. (2007). "Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry". Chem. Res. Toxicol. 20 (9): 1331–1341. doi:10.1021/tx700107z. PMC 2423818. PMID 17702526.
  32. ^ Shou, M; Gonzalez, FJ; Gelboin, HV (December 1996). "Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase". Biochemistry. 35 (49): 15807–13. doi:10.1021/bi962042z. PMID 8961944.
  33. ^ a b Whitlock, JP Jr. (April 1999). "Induction of cytochrome P4501A1". Annual Review of Pharmacology and Toxicology. 39: 103–125. doi:10.1146/annurev.pharmtox.39.1.103. PMID 10331078.
  34. ^ Uno, S.; Dragin, N; Miller, ML; et al. (2008). "Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract". Free Radic Biol Med. 44 (4): 570–83. doi:10.1016/j.freeradbiomed.2007.10.044. PMC 2754765. PMID 17997381.
  35. ^ Do, KN; Fink, LN; Jensen, TE; et al. (2012). "TLR2 controls intestinal carcinogen detoxication by CYP1A1". PLOS ONE. 7 (3): e32309. Bibcode:2012PLoSO...732309D. doi:10.1371/journal.pone.0032309. PMC 3307708. PMID 22442665.
  36. ^ Stribinskis, Vilius; Ramos, Kenneth S. (2006). "Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, a Ubiquitous Environmental Carcinogen". Cancer Res. 66 (5): 2616–20. doi:10.1158/0008-5472.CAN-05-3478. PMID 16510580.
  37. ^ Li, Wentao; Hu, Jinchuan; Adebali, Ogun; et al. (2017-06-27). "Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene". Proceedings of the National Academy of Sciences of the United States of America. 114 (26): 6752–6757. Bibcode:2017PNAS..114.6752L. doi:10.1073/pnas.1706021114. PMC 5495276. PMID 28607059.

External links edit

  • International Chemical Safety Card 0104
  • National Pollutant Inventory – Polycyclic Aromatic Hydrocarbon Fact Sheet
  • . Lung Cancer. Archived from the original on April 14, 2005. Retrieved March 5, 2005.
  • "Levels of Benzopyrene in Burnt toasts". Guardian Unlimited, Special reports: Close encounters. Retrieved March 5, 2005.
  • Karle, I. L. (2004). "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. 101 (6): 1433–8. Bibcode:2004PNAS..101.1433K. doi:10.1073/pnas.0307305101. PMC 341736. PMID 14757823.


January 01, 1970
benzo, pyrene, correct, title, this, article, benzo, pyrene, substitution, brackets, technical, restrictions, benzo, pyrene, polycyclic, aromatic, hydrocarbon, result, incomplete, combustion, organic, matter, temperatures, between, ubiquitous, compound, found,. The correct title of this article is Benzo a pyrene The substitution of any brackets is due to technical restrictions Benzo a pyrene BaP or B a P is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 C 572 F and 600 C 1 112 F The ubiquitous compound can be found in coal tar tobacco smoke and many foods especially grilled meats The substance with the formula C20H12 is one of the benzopyrenes formed by a benzene ring fused to pyrene Its diol epoxide metabolites more commonly known as BPDE react with and bind to DNA resulting in mutations and eventually cancer It is listed as a Group 1 carcinogen by the IARC In the 18th century a scrotal cancer of chimney sweepers the chimney sweeps carcinoma was already known to be connected to soot Benzo a pyrene Skeletal formula Ball and stick model Space filling model Names Preferred IUPAC name Benzo pqr tetraphene 1 Other names Benz a pyreneBenzo a pyrene3 4 Benzpyrene3 4 Benzopyrene3 4 Benz a pyrene3 4 Benzo a pyrenePentacyclo 10 6 2 02 7 09 19 016 20 icosa 1 3 5 7 9 11 13 15 17 19 decaene citation needed Identifiers CAS Number 50 32 8 Y 3D model JSmol Interactive image ChEBI CHEBI 29865 Y ChEMBL ChEMBL31184 Y ChemSpider 2246 Y ECHA InfoCard 100 000 026 EC Number 200 028 5 KEGG C07535 Y PubChem CID 2336 RTECS number DJ3675000 UNII 3417WMA06D UN number 3077 3082 CompTox Dashboard EPA DTXSID2020139 InChI InChI 1S C20H12 c1 2 7 17 15 4 1 12 16 9 8 13 5 3 6 14 10 11 18 17 20 16 19 13 14 h1 12H YKey FMMWHPNWAFZXNH UHFFFAOYSA N YInChI 1 C20H12 c1 2 7 17 15 4 1 12 16 9 8 13 5 3 6 14 10 11 18 17 20 16 19 13 14 h1 12HKey FMMWHPNWAFZXNH UHFFFAOYAQ SMILES c1ccc2c c1 cc3ccc4cccc5c4c3c2cc5 Properties Chemical formula C 20H 12 Molar mass 252 316 g mol 1 Density 1 24 g cm3 25 C Melting point 179 2 C 354 F 452 K Boiling point 495 C 923 F 768 K Solubility in water 0 2 to 6 2 mg L Magnetic susceptibility x 135 7 10 6 cm3 mol Hazards 3 GHS labelling Pictograms Signal word Danger Hazard statements H317 H340 H350 H360 H410 Precautionary statements P201 P202 P261 P272 P273 P280 P281 P302 P352 P308 P313 P321 P333 P313 P363 P391 P405 P501 Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Y verify what is Y N Infobox references Contents 1 Description 2 Sources 3 History 4 Toxicity 4 1 Nervous system 4 2 Immune system 4 3 Reproductive system 4 4 Carcinogenicity 4 5 Interaction with DNA 5 Nucleotide excision repair 6 See also 7 References 8 External linksDescription editBenzo a pyrene BaP is a polycyclic aromatic hydrocarbon found in coal tar with the formula C20H12 The compound is one of the benzopyrenes formed by a benzene ring fused to pyrene and is the result of incomplete combustion at temperatures between 300 C 572 F and 600 C 1 112 F Sources editThe main source of atmospheric BaP is residential wood burning 4 It is also found in coal tar in automobile exhaust fumes especially from diesel engines in all smoke resulting from the combustion of organic material including cigarette smoke and in charbroiled food A 2001 National Cancer Institute study found levels of BaP to be significantly higher in foods that were cooked well done on the barbecue particularly steaks chicken with skin and hamburgers Cooked meat products have been shown to contain up to 4 ng g of BaP 5 and up to 5 5 ng g in fried chicken 6 and 62 6 ng g in overcooked charcoal barbecued beef 7 BaP is discharged in wastewater by industries such as smelters particularly iron and steel mills 8 and aluminium smelters 9 History editIn the 18th century young British chimney sweeps who climbed into chimneys suffered from chimney sweeps carcinoma a scrotal cancer peculiar to their profession and this was connected to the effects of soot in 1775 10 in the first work of occupational cancer epidemiology and also the first connection of any chemical mixture to cancer formation Frequent skin cancers were noted among fuel industry workers in the 19th century In 1933 BaP was determined to be the compound responsible for these cases and its carcinogenicity was demonstrated when skin tumors occurred in laboratory animals repeatedly painted with coal tar 11 BaP has since been identified as a prime carcinogen in cigarette smoke 12 Toxicity edit nbsp Benzo a pyrene showing the base pyrene ring and numbering and ring fusion locations according to IUPAC nomenclature of organic chemistry Nervous system edit Prenatal exposure of BaP in rats is known to affect learning and memory in rodent models Pregnant rats eating BaP were shown to negatively affect the brain function in the late life of their offspring At a time when synapses are first formed and adjusted in strength by activity BaP diminished NMDA receptor dependent nerve cell activity measured as mRNA expression of the NMDA NR2B receptor subunit 13 Immune system edit BaP has an effect on the number of white blood cells inhibiting some of them from differentiating into macrophages the body s first line of defense to fight infections In 2016 the molecular mechanism was uncovered as damage to the macrophage membrane s lipid raft integrity by decreasing membrane cholesterol at 25 This means less immunoreceptors CD32 a member of the Fc family of immunoreceptors could bind to IgG and turn the white blood cell into a macrophage Therefore macrophage membranes become susceptible to bacterial infections 14 Reproductive system edit In experiments with male rats subchronic exposure to inhaled BaP has been shown to generally reduce the function of testicles and epididymis with lower sex steroid testosterone production and sperm production 15 Carcinogenicity edit BaP s metabolites are mutagenic and highly carcinogenic and it is listed as a Group 1 carcinogen by the IARC Chemical agents and related occupations Volume 10 A review of Human Carcinogens IARC Monographs Lyon France 2009 16 In June 2016 BaP was added as benzo def chrysene to the REACH Candidate List of Substances of very high concern for Authorisation 17 Numerous studies since the 1970s have documented links between BaP and cancers 18 It has been more difficult to link cancers to specific BaP sources especially in humans and difficult to quantify risks posed by various methods of exposure inhalation or ingestion 19 A link between vitamin A deficiency and emphysema in smokers was described in 2005 to be due to BaP which induces vitamin A deficiency in rats 20 A 1996 study provided molecular evidence linking components in tobacco smoke to lung cancer BaP was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung tumours 21 Regular consumption of cooked meats has been epidemiologically associated with increased levels of colon cancer 22 although this in itself does not prove carcinogenicity 23 A 2005 NCI study found an increased risk of colorectal adenomas was associated with BaP intake and more strongly with BaP intake from all foods 24 The detoxification enzymes cytochrome P450 1A1 CYP1A1 and cytochrome P450 1B1 CYP1B1 are both protective and necessary for benzo a pyrene toxicity Experiments with strains of mice engineered to remove knockout CYP1A1 and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of BaP and that removing this protection accumulates large concentrations of BaP Unless CYP1B1 is also knocked out toxicity results from the bioactivation of BaP to benzo a pyrene 7 8 dihydrodiol 9 10 epoxide the ultimate toxic compound 25 better source needed Interaction with DNA edit nbsp Metabolism of benzo a pyrene yielding the carcinogenic benzo a pyren 7 8 dihydrodiol 9 10 epoxide nbsp A DNA adduct at center of benzo a pyrene the major mutagen in tobacco smoke 26 Properly speaking BaP is a procarcinogen meaning that its mechanism of carcinogenesis depends on its enzymatic metabolism to BaP diol epoxide 27 It intercalates in DNA and the electrophilic epoxide is attacked by nucleophilic guanine bases forming a bulky guanine adduct 27 nbsp X ray crystallographic and nuclear magnetic resonance structure studies have shown how this binding distorts the DNA 28 by confusing the double helical DNA structure This disrupts the normal process of copying DNA and causes 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 29 There are indications that benzo a pyrene diol epoxide specifically targets the protective p53 gene 30 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 benzo a pyrene diol epoxide inactivates the tumor suppression ability in certain cells leading to cancer Benzo a pyrene 7 8 dihydrodiol 9 10 epoxide is the carcinogenic product of three enzymatic reactions 31 Benzo a pyrene is first oxidized by cytochrome P450 1A1 to form a variety of products including benzo a pyrene 7 8 epoxide 32 This product is metabolized by epoxide hydrolase opening up the epoxide ring to yield benzo a pyrene 7 8 dihydrodiol The ultimate carcinogen is formed after another reaction with cytochrome P450 1A1 to yield the benzo a pyrene 7 8 dihydrodiol 9 10 epoxide It is this diol epoxide that covalently binds to DNA BaP induces cytochrome P450 1A1 CYP1A1 by binding to the AHR aryl hydrocarbon receptor in the cytosol 33 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 33 This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins Seemingly CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo a pyrene to enter portal blood and systemic circulation 34 Intestinal but not hepatic expression of CYP1A1 depends on TOLL like receptor 2 TLR2 35 which is a eukaryotic receptor for bacterial surface structures such as lipoteichoic acid Moreover BaP has been found to activate a transposon LINE1 in humans 36 Nucleotide excision repair editAs illustrated above benzo a pyrene 7 8 dihydrodiol 9 10 epoxide BPDE forms bulky covalent DNA adducts with guanines Most of these adducts can be efficiently eliminated from DNA by the process of nucleotide excision repair 37 Those adducts that are not removed can cause errors during DNA replication leading to carcinogenic mutations See also editBenzopyrene Benzo e pyrene Pyrene a four ring analogue ToxificationReferences edit Henri A Favre Warren H Powell 2013 Nomenclature of Organic Chemistry IUPAC Recommendations and Preferred Names 2013 Royal Society of Chemistry p 232 ISBN 978 0 85404 182 4 William M Haynes 2016 CRC Handbook of Chemistry and Physics 97th ed Boca Raton CRC Press pp 3 42 ISBN 978 1 4987 5429 3 benzo a pyrene pubchem ncbi nlm nih gov Assessment of Benzo alpha pyrene Emissions in the Great Lakes Region PDF pp 23 24 Kazerouni N Sinha R Hsu CH et al 2002 Analysis of 200 food items for benzo a pyrene and estimation of its intake in an epidemiologic study Food and Chemical Toxicology 40 1 423 36 doi 10 1016 S0278 6915 00 00158 7 PMID 11313108 Lee BM Shim GA Aug 2007 Dietary exposure estimation of benzo a pyrene and cancer risk assessment Journal of Toxicology and Environmental Health Part A 70 15 16 1391 4 doi 10 1080 15287390701434182 PMID 17654259 S2CID 21302834 Aygun SF Kabadayi F December 2005 Determination of benzo a pyrene in charcoal grilled meat samples by HPLC with fluorescence detection Int J Food Sci Nutr 56 8 581 5 doi 10 1080 09637480500465436 PMID 16638662 S2CID 35095622 U S Environmental Protection Agency EPA Washington D C 2002 Iron and Steel Manufacturing Point Source Category Code of Federal Regulations 40 CFR Part 420 EPA 1984 Nonferrous Metals Manufacturing Point Source Category Code of Federal Regulations 40 CFR Part 421 Pott Percivall 1775 Chirurgical Observations London England L Hawes W Clarke and R Collins pp 63 68 From p 67 The disease in these people i e chimney sweeps seems to derive its origin from a lodgment of soot in the rugae of the scrotum Cook J W Hewett C L Hieger I 1933 The isolation of a cancer producing Hydrocarbon from coal tar J Chem Soc 1933 395 405 doi 10 1039 jr9330000395 Hecht SS 1999 Tobacco smoke carcinogens and lung cancer J Natl Cancer Inst 91 14 1194 210 doi 10 1093 jnci 91 14 1194 PMID 10413421 McCallister M M Maguire M Ramesh A et al 2008 Prenatal Exposure to Benzo a pyrene Impairs Later Life Cortical Neuronal Function NeuroToxicology 29 5 846 854 doi 10 1016 j neuro 2008 07 008 PMC 2752856 PMID 18761371 Clark RS Pellom ST Booker B et al 2016 Validation of research trajectory 1 of an Exposome framework Exposure to benzo a pyrene confers enhanced susceptibility to bacterial infection Environ Research 146 173 84 Bibcode 2016ER 146 173C doi 10 1016 j envres 2015 12 027 PMC 5523512 PMID 26765097 Ramesh A1 Inyang F Lunstra DD Niaz MS et al Aug 2008 Alteration of fertility endpoints in adult male F 344 rats by subchronic exposure to inhaled benzo a pyrene Exp Toxicol Pathol 60 4 5 269 80 doi 10 1016 j etp 2008 02 010 PMC 3526104 PMID 18499416 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint numeric names authors list link A review of human carcinogens part F chemical agents and related occupations European Chemicals Agency ED 21 2016 ECHA Retrieved 21 June 2016 Kleibohmer W 2001 Polycyclic Aromatic Hydrocarbon PAH Metabolites Environmental Analysis Volume 3 of Handbook of Analytical Separations Elsevier pp 99 122 ISBN 978 0 08 050576 3 Armstrong B Hutchinson E Unwin J Fletcher T 2004 Lung Cancer Risk After Exposure to Polycyclic Aromatic Hydrocarbons A Review and Meta Analysis Environmental Health Perspectives 112 9 970 978 doi 10 1289 ehp 6895 PMC 1247189 PMID 15198916 Benzopyrene and Vitamin A deficiency Researcher links cigarettes vitamin A and emphysema Retrieved March 5 2005 Denissenko M F Pao A Tang M Pfeifer G P 1996 10 18 Preferential formation of benzo a pyrene adducts at lung cancer mutational hotspots in P53 Science 274 5286 430 432 Bibcode 1996Sci 274 430D doi 10 1126 science 274 5286 430 PMID 8832894 S2CID 3589066 Le Marchand L Hankin JH Pierce LM et al September 2002 Well done red meat metabolic phenotypes and colorectal cancer in Hawaii Mutat Res 506 507 205 14 doi 10 1016 s0027 5107 02 00167 7 PMID 12351160 Truswell AS Mar 2002 Meat consumption and cancer of the large bowel European Journal of Clinical Nutrition 56 Suppl 1 S19 24 doi 10 1038 sj ejcn 1601349 PMID 11965518 S2CID 23886438 Sinha Rashmi Kulldorff Martin Gunter Marc J et al August 2005 Dietary benzo a pyrene intake and risk of colorectal adenoma Cancer Epidemiology Biomarkers amp Prevention 14 8 2030 2034 doi 10 1158 1055 9965 EPI 04 0854 PMID 16103456 S2CID 33819830 Data presented by Daniel W Nebert in research seminars 2007 Created from PDB 1JDG Archived 2008 09 22 at the Wayback Machine a b Bogdan Dennis Paul February 1 1973 Interactions Of Benzopyrene And Nucleic Acids In The Presence Of A Mixed Function Oxidase System Ph D Dissertation requires login ISBN 979 8661021359 ProQuest 302781013 Retrieved May 9 2021 a href Template Cite book html title Template Cite book cite book a work ignored help Volk David E Thiviyanathan Varatharasa Rice Jeffrey S et al 2003 02 18 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 42 6 1410 1420 doi 10 1021 bi026745u PMID 12578353 Eaton D L Gallagher E P 1994 Mechanisms of aflatoxin carcinogenesis Annual Review of Pharmacology and Toxicology 34 135 172 doi 10 1146 annurev pa 34 040194 001031 PMID 8042848 Pfeifer Gerd P Denissenko Mikhail F Olivier Magali et al 2002 10 21 Tobacco smoke carcinogens DNA damage and p53 mutations in smoking associated cancers Oncogene 21 48 7435 7451 doi 10 1038 sj onc 1205803 PMID 12379884 S2CID 6134471 Jiang Hao Gelhaus Stacy L Mangal Dipti et al 2007 Metabolism of Benzo a pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography Mass Spectrometry Chem Res Toxicol 20 9 1331 1341 doi 10 1021 tx700107z PMC 2423818 PMID 17702526 Shou M Gonzalez FJ Gelboin HV December 1996 Stereoselective epoxidation and hydration at the K region of polycyclic aromatic hydrocarbons by cDNA expressed cytochromes P450 1A1 1A2 and epoxide hydrolase Biochemistry 35 49 15807 13 doi 10 1021 bi962042z PMID 8961944 a b Whitlock JP Jr April 1999 Induction of cytochrome P4501A1 Annual Review of Pharmacology and Toxicology 39 103 125 doi 10 1146 annurev pharmtox 39 1 103 PMID 10331078 Uno S Dragin N Miller ML et al 2008 Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract Free Radic Biol Med 44 4 570 83 doi 10 1016 j freeradbiomed 2007 10 044 PMC 2754765 PMID 17997381 Do KN Fink LN Jensen TE et al 2012 TLR2 controls intestinal carcinogen detoxication by CYP1A1 PLOS ONE 7 3 e32309 Bibcode 2012PLoSO 732309D doi 10 1371 journal pone 0032309 PMC 3307708 PMID 22442665 Stribinskis Vilius Ramos Kenneth S 2006 Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo a pyrene a Ubiquitous Environmental Carcinogen Cancer Res 66 5 2616 20 doi 10 1158 0008 5472 CAN 05 3478 PMID 16510580 Li Wentao Hu Jinchuan Adebali Ogun et al 2017 06 27 Human genome wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo a pyrene Proceedings of the National Academy of Sciences of the United States of America 114 26 6752 6757 Bibcode 2017PNAS 114 6752L doi 10 1073 pnas 1706021114 PMC 5495276 PMID 28607059 External links editInternational Chemical Safety Card 0104 National Pollutant Inventory Polycyclic Aromatic Hydrocarbon Fact Sheet Lung cancer as consequence by Benzopyrene in smokers Lung Cancer Archived from the original on April 14 2005 Retrieved March 5 2005 Levels of Benzopyrene in Burnt toasts Guardian Unlimited Special reports Close encounters Retrieved March 5 2005 Karle I L 2004 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 101 6 1433 8 Bibcode 2004PNAS 101 1433K doi 10 1073 pnas 0307305101 PMC 341736 PMID 14757823 Retrieved from https en wikipedia org w index php title Benzo a pyrene amp oldid 1202023891, wikipedia, wiki, book, books, library,

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