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Revision as of 22:26, 6 August 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEBI').← Previous edit Latest revision as of 13:19, 5 November 2024 edit undoQuanto6676 (talk | contribs)4 editsm Back when I originally made my wikipedia account as a teenager I made some minor changes to this page because I couldn't understand the words that were written. I have now come back to erase the mistakes I made and add the original words back, as I had no good reason to initially edit them back then.Tag: Visual edit 
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{{Short description|Carcinogenic compound found in smoke and soot}}
{{DISPLAYTITLE:Benzo(''a'')pyrene}} {{DISPLAYTITLE:Benzo(''a'')pyrene}}
{{correct title|reason=bracket|Benzopyrene}} {{Correct title|reason=bracket|edit=substitution|Benzopyrene}}
{{chembox {{Chembox
| Watchedfields = changed
| verifiedrevid = 410332682
| verifiedrevid =443416124
| Name = '''Benzopyrene'''
| ImageFile = Benzo-a-pyrene.svg | Name =Benzopyrene
| ImageFile =Benzo-a-pyrene.svg
| ImageSize = 200px
| ImageSize =
| ImageFile1 = Benzo(a)pyrene-3D-balls-2.png
| ImageCaption = ]
| ImageSize1 = 200px
| ImageName = Benzopyrene | ImageName =Benzopyrene
| IUPACName = Benzopyrene | ImageFile1 = Benzo(a)pyrene-from-xtal-3D-bs-17.png
| ImageSize1 =
| Section1 = {{Chembox Identifiers
| ImageCaption1 = ]
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ImageFile2 = Benzo(a)pyrene-from-xtal-3D-sf.png
| ImageCaption2 = ]
| PIN =Benzotetraphene<ref name="bluebook">{{cite book | author=Henri A. Favre, Warren H. Powell | title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 | year=2013 | publisher=] | isbn = 978-0-85404-182-4 | page=232}}</ref>
| OtherNames = {{ubl|Benzpyrene|Benzopyrene|3,4-Benzpyrene|3,4-Benzopyrene|3,4-Benzpyrene|3,4-Benzopyrene|Pentacycloicosa-1,3,5,7,9,11,13,15,17,19-decaene{{citation needed|date=May 2019}}}}
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2246 | ChemSpiderID = 2246
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C07535 | KEGG =C07535
| 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 | 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
| InChIKey = FMMWHPNWAFZXNH-UHFFFAOYAQ | InChIKey =FMMWHPNWAFZXNH-UHFFFAOYAQ
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 31184 | ChEMBL =31184
| PubChem = 2336
| RTECS = DJ3675000
| UNNumber = 3077, 3082
| UNII = 3417WMA06D
| EINECS = 200-028-5
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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 | StdInChI =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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FMMWHPNWAFZXNH-UHFFFAOYSA-N | StdInChIKey =FMMWHPNWAFZXNH-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}} | CASNo_Ref = {{cascite|correct|CAS}}
| CASNo=50-32-8 | CASNo =50-32-8
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 29865
| ChEBI =29865
| SMILES = c1ccc2c(c1)cc3ccc4cccc5c4c3c2cc5
| SMILES =c1ccc2c(c1)cc3ccc4cccc5c4c3c2cc5}}
|Section2={{Chembox Properties
| C=20 | H=12
| Density =1.24 g/cm<sup>3</sup> (25 °C)
| MeltingPtC = 179 <ref name="crc97">{{cite book | author=William M. Haynes | title=CRC Handbook of Chemistry and Physics | edition=97th | year=2016 | publisher=CRC Press | location=Boca Raton | isbn=978-1-4987-5429-3 | pages=3–42 | url=https://books.google.com/books?id=VVezDAAAQBAJ}}</ref>
| MeltingPt_notes =
| BoilingPtC = 495
| BoilingPt_notes =
| Solubility =0.2 to 6.2 μg/L
| MagSus = -135.7·10<sup>−6</sup> cm<sup>3</sup>/mol}}
| Section7 = {{Chembox Hazards
| Hazards_ref =<ref>{{cite web|title=benzopyrene|url=https://pubchem.ncbi.nlm.nih.gov/compound/2336#section=Hazards-Identification|website=pubchem.ncbi.nlm.nih.gov|language=en}}</ref>
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}} }}
| Section2 = {{Chembox Properties
|C=20|H=12
| Density = 1.24 g/cm³ (25 °C)
| MeltingPt = 179 °C
| BoilingPt = 495 °C
| Solubility = 0.11 mg/L (25 °C)
}}
}} }}


'''Benzopyrene''' ('''B''a''P''' or '''BP''') is a ] and the result of incomplete combustion of ] at temperatures between {{convert|300|°C|°F}} and {{convert|600|°C|°F}}. The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C<sub>20</sub>H<sub>12</sub> is one of the ]s, formed by a ] ring fused to ]. Its ] ] metabolites, more commonly known as BPDE, react with and bind to ], resulting in mutations and eventually cancer. It is listed as a ] by the ]. In the 18th century a scrotal cancer of chimney sweepers, the ], was already known to be connected to soot.
'''Benzopyrene''', C<sub>20</sub>H<sub>12</sub>, is a five-ring ] whose metabolites are ]ic and highly ]ic. Benzopyrene is listed as a ] by the ]. It belongs to a class of polycyclic aromatic compounds known as ]s, which consist of a ] ring fused to a ] molecule. Benzopyrene is a product of incomplete ] at ]s between 300 and 600 °]. Benzopyrene was determined in 1933 to be the component of ] responsible for the first recognized occupation-associated cancers, the ] (] of the ]) suffered by ] in 18th century England. In the 19th century, high incidences of ] were noted among fuel industry workers. By the early 20th century, the toxicity of benzopyrene was demonstrated when ] were produced in laboratory animals by repeatedly painting them with ].


== Description ==
==Sources of Benzopyrene==
Benzopyrene (B''a''P) is a ] found in ] with the formula C<sub>20</sub>H<sub>12</sub>. The compound is one of the ]s, formed by a ] ring fused to ], and is the result of incomplete combustion at temperatures between {{convert|300|°C|°F}} and {{convert|600|°C|°F}}.
Benzopyrene is found in ], in ] (especially from ]s), in all smoke resulting from the combustion of organic material (including ]), and in ]ed food. Recent studies have revealed that levels of benzopyrene in burnt ] are significantly higher than once thought,{{Citation needed|date=June 2008}} although it is unproven whether burnt toast is itself ]. Cooked meat products, regular consumption of which has been epidemiologically associated with increased levels of ]<ref>Le Marchand L, Hankin JH, Pierce LM, Sinha R, Nerurkar PV, Franke AA, Wilkens LR, Kolonel LN, Donlon T, Seifried A, Custer LJ, Lum-Jones A, Chang W. Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii. ''Mutation Research''. 2002 Sep 30;506-507:205-14. PMID 12351160</ref> (although this in itself does not ''prove'' ]),<ref>Truswell AS. Meat consumption and cancer of the large bowel. ''European Journal of Clinical Nutrition''. 2002 Mar;56 Suppl 1:S19-24. PMID 11965518</ref> have been shown to contain up to 4&nbsp;ng/g of benzopyrene,<ref>Kazerouni N, Sinha R, Hsu CH, Greenberg A, Rothman N. Analysis of 200 food items for benzopyrene and estimation of its intake in an epidemiologic study. ''Food and Chemical Toxicology'' 2002;40(1):133. doi:10.1016/S0278-6915(00)00158-7</ref> and up to 5.5&nbsp;ng/g in fried chicken<ref>Lee BM, Shim GA. Dietary exposure estimation of benzopyrene and cancer risk assessment. ''Journal of Toxicology and Environmental Health Part A''. 2007 Aug;70(15-16):1391-4. PMID 17654259</ref> and 62.6&nbsp;ng/g in overcooked charcoal barbecued beef.<ref>Aygün SF, Kabadayi F. Determination of benzopyrene in charcoal grilled meat samples by HPLC with fluorescence detection. ''International Journal of Food Sciences and Nutrition''. 2005 Dec;56(8):581-5. PMID 16638662</ref>


==Toxicity== == Sources ==
The main source of atmospheric B''a''P is residential wood burning.<ref>{{cite web |title=Assessment of Benzo-alpha-pyrene Emissions in the Great Lakes Region |pages=23–24 |url=http://www.epa.gov/ttnchie1/conference/ei20/session10/asoehl_pres.pdf}}</ref> It is also found in ], in ] (especially from ]s), in all smoke resulting from the combustion of organic material (including ]), and in ]ed food.
A 2001 ] study found levels of B''a''P to be significantly higher in foods that were cooked well-done on the ], particularly ]s, ] with skin, and ]s: Cooked meat products have been shown to contain up to 4&nbsp;ng/g of B''a''P,<ref>{{cite journal | last1 = Kazerouni | first1 = N | last2 = Sinha | first2 = R | last3 = Hsu | first3 = CH | last4 = Greenberg | first4 = A | last5 = Rothman | first5 = N |display-authors=3 | year = 2002 | title = Analysis of 200 food items for benzopyrene and estimation of its intake in an epidemiologic study | journal = ] | volume = 40 | issue = 1| pages = 423–36 | doi = 10.1016/S0278-6915(00)00158-7 | pmid = 11313108 }}</ref> and up to 5.5&nbsp;ng/g in fried chicken<ref>{{cite journal | last1 = Lee | first1 = BM | last2 = Shim | first2 = GA | date = Aug 2007 | title = Dietary exposure estimation of benzopyrene and cancer risk assessment | journal = Journal of Toxicology and Environmental Health Part A | volume = 70 | issue = 15–16| pages = 1391–4 | pmid = 17654259 | doi=10.1080/15287390701434182| s2cid = 21302834 }}</ref> and 62.6&nbsp;ng/g in overcooked charcoal barbecued beef.<ref>{{cite journal | pmid = 16638662 | doi=10.1080/09637480500465436 | volume=56 | issue=8 | title=Determination of benzopyrene in charcoal grilled meat samples by HPLC with fluorescence detection | date=December 2005 | journal=Int J Food Sci Nutr | pages=581–5 | last1 = Aygün | first1 = SF | last2 = Kabadayi | first2 = F| s2cid=35095622 }}</ref>

B''a''P is discharged in wastewater by industries such as ]s, particularly ] mills<ref>U.S. Environmental Protection Agency (EPA), Washington, D.C. (2002). "Iron and Steel Manufacturing Point Source Category." ''Code of Federal Regulations,'' .</ref> and ] smelters.<ref>EPA (1984). "Nonferrous Metals Manufacturing Point Source Category." ''Code of Federal Regulations,'' .</ref>

== History ==
In the 18th century, young British ]s who climbed into chimneys suffered from ], a scrotal cancer peculiar to their profession, and this was connected to the effects of ] in 1775,<ref>{{cite book |last1=Pott |first1=Percivall |title=Chirurgical Observations … |date=1775 |publisher=L. Hawes, W. Clarke, and R. Collins |location=London, England |pages=63–68 |url=https://books.google.com/books?id=15htmgEACAAJ&pg=PA63}} From p. 67: "The disease, in these people , seems to derive its origin from a lodgment of soot in the rugae of the scrotum, … "</ref> in the first work of ] epidemiology and also the first connection of any ] to cancer formation. Frequent ]s were noted among fuel industry workers in the 19th century. In 1933, B''a''P 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.<ref>{{cite journal | last1 = Cook | first1 = J. W. | last2 = Hewett | first2 = C. L. | last3 = Hieger | first3 = I. | year = 1933 | title = The isolation of a cancer producing Hydrocarbon from coal tar | url = https://pubs.rsc.org/en/Content/ArticleLanding/1933/JR/jr9330000395 | journal = J. Chem. Soc. | volume = 1933 | pages = 395–405 | doi = 10.1039/jr9330000395 }}</ref> B''a''P has since been identified as a prime carcinogen in cigarette smoke.<ref>{{cite journal | last1 = Hecht | first1 = SS | year = 1999 | title = Tobacco smoke carcinogens and lung cancer | journal = J Natl Cancer Inst | volume = 91 | issue = 14| pages = 1194–210 | pmid = 10413421 | doi = 10.1093/jnci/91.14.1194 | doi-access = free }}</ref>

== Toxicity ==
pyrene, showing the base ] ring and numbering and ring fusion locations according to ].]] pyrene, showing the base ] ring and numbering and ring fusion locations according to ].]]
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 ] recently discovered a link between ] deficiency and ] in ].<ref>{{Cite web| title=Benzopyrene and Vitamin A deficiency | work=Researcher links cigarettes, vitamin A and emphysema | url=http://www.tobacco.org/news/171229.html| accessdate=March 5, 2005 }}</ref> Benzopyrene was found to be behind the link, since it induces vitamin A deficiency in rats.


=== Nervous system ===
In 1996, a study was published that provided the clear molecular evidence conclusively linking components in ] to ].<ref>Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzopyrene adducts at lung cancer mutational hotspots in P53. Science. 1996 October 18;274(5286):430-2.</ref> Benzopyrene, found in ] (including ]), was shown to cause genetic damage in lung cells that was identical to the damage observed in the ] of most malignant ] tumours.
] of B''a''P in rats is known to affect learning and memory in rodent models. Pregnant rats eating B''a''P were shown to negatively affect the brain function in the late life of their offspring. At a time when ]s are first formed and adjusted in strength by activity, B''a''P diminished ] receptor-dependent nerve cell activity measured as mRNA expression of the NMDA ] receptor subunit.<ref>{{Cite journal|pmc=2752856|year=2008|last1=McCallister|first1=M. M.|title=Prenatal Exposure to Benzopyrene Impairs Later-Life Cortical Neuronal Function|journal=NeuroToxicology|volume=29|issue=5|pages=846–854|last2=Maguire|first2=M|last3=Ramesh|first3=A|last4=Aimin|first4=Q|last5=Liu|first5=S|last6=Khoshbouei|first6=H|last7=Aschner|first7=M|last8=Ebner|first8=F. F.|last9=Hood|first9=D. B.|display-authors=3|doi=10.1016/j.neuro.2008.07.008|pmid=18761371}}.</ref>


=== Immune system ===
A 2001 ] study found levels of benzopyrene to be significantly higher in foods that were cooked well-done on the ], particularly ]s, ] with skin, and ]s. {{Citation needed|date=February 2007}}<ref>http://cebp.aacrjournals.org/content/14/8/2030.full</ref> ]ese scientists showed that cooked ] contains ], chemicals that are capable of altering the chemical structure of ] {{Citation needed|date=February 2007}}. However, the foods themselves are not necessarily ], even if they contain trace amounts of carcinogens, because the gastrointestinal tract protects itself against ]s by shedding its outer layer continuously. Furthermore, detoxification enzymes, such as ] 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.
B''a''P has an effect on the number of ]s, inhibiting some of them from differentiating into ]s, 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 ] (a member of the Fc family of immunoreceptors) could bind to ] and turn the white blood cell into a macrophage. Therefore, macrophage membranes become susceptible to bacterial infections.<ref>{{cite journal | title=Validation of research trajectory 1 of an Exposome framework: Exposure to benzopyrene confers enhanced susceptibility to bacterial infection. | vauthors=Clark RS, Pellom ST, Booker B, Ramesh A, Zhang T, Shanker A, Maguire M, Juarez PD, Patricia MJ, Langston MA, Lichtveld MY, Hood DB |display-authors=3| journal=Environ Research | year=2016 | volume=146 | pages=173–84 | doi=10.1016/j.envres.2015.12.027 | pmid=26765097| pmc=5523512 | bibcode=2016ER....146..173C }}</ref>


=== Reproductive system ===
A recent study has found that ] (]) and ] (]) are both protective and, confusingly, necessary for benzopyrene toxicity. Experiments with strains of mice engineered to remove (]) ] and ] 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 ] is also knocked out, benzopyrene toxicity results from the ] of benzopyrene to the ultimate toxic compound, benzopyrene -7,8-dihydrodiol-9,10-epoxide (see below).<ref>Data presented by Daniel W. Nebert in research seminars 2007</ref>
In experiments with male rats, ] exposure to inhaled B''a''P has been shown to generally reduce the function of testicles and ] with lower sex steroid/testosterone production and sperm production.<ref>{{cite journal | last1 = Ramesh A1 | first1 = Inyang F | last2 = Lunstra | first2 = DD | last3 = Niaz | first3 = MS | last4 = Kopsombut | first4 = P | last5 = Jones | first5 = KM | last6 = Hood | first6 = DB | last7 = Hills | first7 = ER | last8 = Archibong | first8 = AE |display-authors=3| date = Aug 2008 | title = Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene | journal = Exp Toxicol Pathol | volume = 60 | issue = 4–5| pages = 269–80 | doi = 10.1016/j.etp.2008.02.010 | pmc = 3526104 | pmid = 18499416 }}</ref>


=== Carcinogenicity ===
==Interaction with DNA==
B''a''P's metabolites are ]ic and highly ]ic, and it is listed as a ] by the ]. Chemical agents and related occupations, Volume 10, A review of Human Carcinogens, IARC Monographs, Lyon France 2009 <ref>A review of human carcinogens—part F: chemical agents and related occupations</ref>

In June 2016, B''a''P was added as benzochrysene to the ] Candidate List of ] for Authorisation.<ref>{{cite web|last1=European Chemicals Agency|title=ED/21/2016|url=http://echa.europa.eu/documents/10162/4b054c5b-8511-4a30-8ef8-35ab143b4fd0|website=ECHA|access-date=21 June 2016}}</ref>

Numerous studies since the 1970s have documented links between B''a''P and cancers.<ref>{{cite book|chapter-url = https://books.google.com/books?id=Fw_G7Sk382IC&q=Benzo%28a%29pyrene-7%2C8-dihydrodiol-9%2C10-epoxide+cas&pg=PA102|first = W.|last = Kleiböhmer|publisher = ]|year = 2001|chapter = Polycyclic Aromatic Hydrocarbon (PAH) Metabolites|pages = 99–122|title = Environmental Analysis (Volume 3 of Handbook of Analytical Separations)|isbn = 978-0-08-050576-3}}</ref> It has been more difficult to link cancers to specific B''a''P sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion).<ref>{{cite journal | title=Lung Cancer Risk After Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis | journal=Environmental Health Perspectives | volume=112 | issue=9 | pages=970–978 | pmc=1247189 | year=2004 | last1=Armstrong | first1=B. | last2=Hutchinson | first2=E. | last3=Unwin | first3=J. | last4=Fletcher | first4=T. | pmid=15198916 | doi=10.1289/ehp.6895 }}</ref> A link between ] deficiency and ] in ] was described in 2005 to be due to B''a''P, which induces vitamin A deficiency in rats.<ref>{{Cite web| title=Benzopyrene and Vitamin A deficiency | work=Researcher links cigarettes, vitamin A and emphysema | url=http://www.tobacco.org/news/171229.html| access-date=March 5, 2005 }}</ref>

A 1996 study provided molecular evidence linking components in ] to ]. B''a''P was shown to cause genetic damage in lung cells that was identical to the damage observed in the ] of most malignant ] tumours.<ref>{{Cite journal |last1=Denissenko |first1=M. F. |last2=Pao |first2=A. |last3=Tang |first3=M. |last4=Pfeifer |first4=G. P. |date=1996-10-18 |title=Preferential formation of benzopyrene adducts at lung cancer mutational hotspots in P53 |journal=Science |volume=274 |issue=5286 |pages=430–432 |doi=10.1126/science.274.5286.430 |pmid=8832894|bibcode=1996Sci...274..430D |s2cid=3589066 }}</ref>

Regular consumption of ] has been epidemiologically associated with increased levels of ]<ref>{{cite journal | pmid = 12351160 | volume=506–507 | title=Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii | date=September 2002 | journal=Mutat. Res. | pages=205–14 | last1 = Le Marchand | first1 = L | last2 = Hankin | first2 = JH | last3 = Pierce | first3 = LM | display-authors = etal | doi=10.1016/s0027-5107(02)00167-7}}</ref> (although this in itself does not ''prove'' carcinogenicity),<ref>{{cite journal | last1 = Truswell | first1 = AS | date = Mar 2002 | title = Meat consumption and cancer of the large bowel | journal = European Journal of Clinical Nutrition | volume = 56 | issue = Suppl 1| pages = S19–24 | pmid = 11965518 | doi=10.1038/sj.ejcn.1601349| s2cid = 23886438 | doi-access = }}</ref>
A 2005 NCI study found an increased risk of ]s was associated with B''a''P intake, and more strongly with B''a''P intake from all foods.<ref>{{Cite journal |last1=Sinha |first1=Rashmi |last2=Kulldorff |first2=Martin |last3=Gunter |first3=Marc J. |last4=Strickland |first4=Paul |last5=Rothman |first5=Nathaniel |display-authors=3|date=August 2005 |title=Dietary benzopyrene intake and risk of colorectal adenoma |url=https://aacrjournals.org/cebp/article/14/8/2030/258146/Dietary-Benzo-a-Pyrene-Intake-and-Risk-of |journal=Cancer Epidemiology, Biomarkers & Prevention |volume=14 |issue=8 |pages=2030–2034 |doi=10.1158/1055-9965.EPI-04-0854 |pmid=16103456|s2cid=33819830 |doi-access=free }}</ref>

The detoxification enzymes cytochrome P450 ] and cytochrome P450 ] are both protective and necessary for benzopyrene toxicity. Experiments with strains of mice engineered to remove (]) CYP1A1 and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of B''a''P, and that removing this protection accumulates large concentrations of B''a''P. Unless CYP1B1 is also knocked out, toxicity results from the ] of B''a''P to benzopyrene -7,8-dihydrodiol-9,10-epoxide, the ultimate toxic compound.<ref>Data presented by ] in research seminars 2007</ref>{{better source|date=July 2016}}

=== Interaction with DNA ===
</nowiki>pyrene yielding the ] benzo<nowiki></nowiki>pyren-7,8-dihydrodiol-9,10-epoxide.]] </nowiki>pyrene yielding the ] benzo<nowiki></nowiki>pyren-7,8-dihydrodiol-9,10-epoxide.]]
] (at center) of benzopyrene, the major ] in ].<ref>Created from </ref>]] ] (at center) of benzopyrene, the major ] in ].<ref>Created from {{Webarchive|url=https://web.archive.org/web/20080922150848/http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG |date=2008-09-22 }}</ref>]]
Properly speaking, B''a''P is a ], meaning that its mechanism of ] depends on its enzymatic metabolism to B''a''P ] ]<ref name="DB-19730201">{{cite thesis |last=Bogdan |first=Dennis Paul|title=Interactions Of Benzopyrene And Nucleic Acids In The Presence Of A Mixed-Function Oxidase System - Ph.D. Dissertation (requires login). |url=https://www.proquest.com/docview/302781013 |id={{ProQuest|302781013}} |isbn=979-8661021359 |date=February 1, 1973 |publisher=] |access-date=May 9, 2021 }}</ref> It ] in ], and the electrophilic epoxide is attacked by nucleophilic ] bases, forming a bulky guanine adduct.<ref name="DB-19730201" />
]


] and ] structure studies have shown how this binding distorts the DNA<ref>{{Cite journal |last1=Volk |first1=David E. |last2=Thiviyanathan |first2=Varatharasa |last3=Rice |first3=Jeffrey S. |last4=Luxon |first4=Bruce A. |last5=Shah |first5=Jamshed H. |last6=Yagi |first6=Haruhiko |last7=Sayer |first7=Jane M. |last8=Yeh |first8=Herman J. C. |last9=Jerina |first9=Donald M. |last10=Gorenstein |first10=David G. |display-authors=3|date=2003-02-18 |title=Solution structure of a cis-opened (10R)-N6-deoxyadenosine adduct of (9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzopyrene in a DNA duplex |journal=Biochemistry |volume=42 |issue=6 |pages=1410–1420 |doi=10.1021/bi026745u |pmid=12578353}}</ref> by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of ] after exposure. This mechanism of action is similar to that of ] which binds to the N7 position of guanine.<ref>{{Cite journal |last1=Eaton |first1=D. L. |last2=Gallagher |first2=E. P. |date=1994 |title=Mechanisms of aflatoxin carcinogenesis |journal=Annual Review of Pharmacology and Toxicology |volume=34 |pages=135–172 |doi=10.1146/annurev.pa.34.040194.001031 |pmid=8042848}}</ref>
Properly speaking, benzopyrene is a ], meaning that the mechanism of ] of benzopyrene depends on enzymatic metabolism of benzopyrene to the ultimate mutagen, benzopyrene diol epoxide, pictured above at right. This molecule ] in ], ] bonding to the ] ] ]s at the N2 position. ] and ] structure studies show that this binding distorts the DNA,<ref>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-tetrahydrobenzopyrene in a DNA duplex. Biochemistry. 2003 February 18;42(6):1410-20.</ref> 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 ] after exposure. This mechanism of action is similar to that of ] which binds to the N7 position of guanine.<ref>Eaton DL, Gallagher EP. Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol. 1994;34:135-72.</ref>


There are indications that benzopyrene diol epoxide specifically targets the protective ] gene.<ref>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.</ref> This gene is a ] that regulates the ] and hence functions as a ]. By inducing G (]) to T (]) ]s in transversion hotspots within ], there is a probability that benzopyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer. There are indications that benzopyrene diol epoxide specifically targets the protective ] gene.<ref>{{Cite journal |last1=Pfeifer |first1=Gerd P. |last2=Denissenko |first2=Mikhail F. |last3=Olivier |first3=Magali |last4=Tretyakova |first4=Natalia |last5=Hecht |first5=Stephen S. |last6=Hainaut |first6=Pierre |display-authors=3|date=2002-10-21 |title=Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers |journal=Oncogene |volume=21 |issue=48 |pages=7435–7451 |doi=10.1038/sj.onc.1205803 |pmid=12379884|s2cid=6134471 }}</ref> This gene is a ] that regulates the ] and hence functions as a ]. By inducing G (]) to T (]) ]s in transversion hotspots within ], there is a probability that benzopyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.


Benzopyrene-7,8-dihydrodiol-9,10-epoxide is the carcinogenic product of three enzymatic reactions:<ref>Hao Jiang, Stacy L. Gelhaus, Dipti Mangal, Ronald G. Harvey, Ian A. Blair, Trevor M. Penning: Metabolism of Benzopyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry, ''Chem. Res. Toxicol.'', 2007, 20 (9), pp 1331–1341 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423818/</ref> pyrene-7,8-dihydrodiol-9,10-epoxide]] is the carcinogenic product of three enzymatic reactions:<ref>{{cite journal | last1 = Jiang | first1 = Hao | last2 = Gelhaus | first2 = Stacy L. | last3 = Mangal | first3 = Dipti | last4 = Harvey | first4 = Ronald G. | last5 = Blair | first5 = Ian A. | last6 = Penning | first6 = Trevor M. |display-authors=3| year = 2007 | title = Metabolism of Benzopyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry | journal = Chem. Res. Toxicol. | volume = 20 | issue = 9| pages = 1331–1341 | pmc=2423818 | pmid=17702526 | doi=10.1021/tx700107z}}</ref>
:# Benzopyrene is first oxidized by ]1A1 to form a variety of products, including (+)benzopyrene-7,8-epoxide.<ref>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</ref> # Benzopyrene is first oxidized by ] ] to form a variety of products, including (+)benzopyrene-7,8-epoxide.<ref>{{cite journal | last1 = Shou | first1 = M | last2 = Gonzalez | first2 = FJ | last3 = Gelboin | first3 = HV |author3-link=Harry Gelboin | date = December 1996 | title = Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase | journal = Biochemistry | volume = 35 | issue = 49| pages = 15807–13 | doi=10.1021/bi962042z | pmid=8961944}}</ref>
:# This product is metabolized by ], opening up the ] ring to yield (-)benzopyrene-7,8-dihydrodiol. # This product is metabolized by ], opening up the ] ring to yield (&minus;)benzopyrene-7,8-dihydrodiol.
:# The ultimate ] is formed after another reaction with ]1A1 to yield the (+)benzopyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA. # The ultimate carcinogen is formed after another reaction with ] 1A1 to yield the (+)benzopyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.


Benzopyrene induces ]1A1 (CYP1A1) by binding to the AHR (]) in the cytosol.<ref name = "Whitlock">{{Cite journal| last = Whitlock | first = JP Jr. | authorlink = | coauthors = | title = Induction of cytochrome P4501A1 | journal = Annual Review of Pharmacology and Toxicology | volume = 39 | issue = | pages = 103–125 | publisher = | location = |date = April 1999| url = | doi = 10.1146/annurev.pharmtox.39.1.103 | id = | accessdate = 2008-11-22 | pmid = 10331078}}</ref> Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (]) and then binds ] (XREs) in DNA located upstream of certain genes. This process increases ] of certain genes, notably ''CYP1A1'', followed by increased CYP1A1 protein production.<ref name = "Whitlock"/> This process is similar to induction of CYP1A1 by certain ]s and ]. B''a''P induces cytochrome P450 1A1 (CYP1A1) by binding to the AHR (]) in the cytosol.<ref name="Whitlock">{{Cite journal| last = Whitlock | first = JP Jr. | title = Induction of cytochrome P4501A1 | journal = Annual Review of Pharmacology and Toxicology | volume = 39 | pages = 103–125 |date = April 1999| doi = 10.1146/annurev.pharmtox.39.1.103 | pmid = 10331078}}</ref> Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (]) and then binds ] (XREs) in DNA located upstream of certain genes. This process increases ] of certain genes, notably ''CYP1A1'', followed by increased CYP1A1 protein production.<ref name="Whitlock" /> This process is similar to induction of CYP1A1 by certain ]s and ]. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzopyrene to enter portal blood and systemic circulation.<ref>{{cite journal |last1=Uno |first1=S. |year=2008 |title=Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract.|journal=Free Radic Biol Med |volume=44 |issue=4 |pages=570–83|pmid=17997381 |doi= 10.1016/j.freeradbiomed.2007.10.044|last2=Dragin|first2=N |last3=Miller |first3=ML |pmc=2754765|display-authors=etal}}</ref> Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (]),<ref>{{Cite journal| last1 = Do| first1 = KN |last2=Fink|first2=LN |last3=Jensen |first3=TE |last4=Gautier |first4=L | last5=Parlesak |first5=A |display-authors=3|year=2012 |title = TLR2 controls intestinal carcinogen detoxication by CYP1A1. | journal = PLOS ONE| volume = 7 | issue = 3 | pages = e32309 | doi = 10.1371/journal.pone.0032309 | pmid = 22442665 | pmc=3307708| bibcode = 2012PLoSO...732309D | doi-access = free }}</ref> which is a eukaryotic receptor for bacterial surface structures such as ].


Recently, benzopyrene has been found to activate a transposon, LINE1, in humans.<ref>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).</ref> Moreover, B''a''P has been found to activate a transposon, ], in humans.<ref>{{cite journal | last1 = Stribinskis | first1 = Vilius | last2 = Ramos | first2 = Kenneth S. | year = 2006 | title = Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, a Ubiquitous Environmental Carcinogen | journal = Cancer Res | volume = 66 | issue = 5| pages = 2616–20 | doi = 10.1158/0008-5472.CAN-05-3478 | pmid = 16510580 | doi-access = free }}</ref>


==Nucleotide excision repair==
==See also==
As illustrated above, (+)benzopyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) forms bulky covalent ]s with ]s. Most of these adducts can be efficiently eliminated from DNA by the process of ].<ref>{{Cite journal |last1=Li |first1=Wentao |last2=Hu |first2=Jinchuan |last3=Adebali |first3=Ogun |last4=Adar |first4=Sheera |last5=Yang |first5=Yanyan |last6=Chiou |first6=Yi-Ying |last7=Sancar |first7=Aziz |display-authors=3|date=2017-06-27 |title=Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzopyrene |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=114 |issue=26 |pages=6752–6757 |doi=10.1073/pnas.1706021114 |pmc=5495276 |pmid=28607059|bibcode=2017PNAS..114.6752L |doi-access=free }}</ref> Those adducts that are not removed can cause errors during ] leading to carcinogenic ]s.

== See also ==
* ] * ]
* pyrene]] * pyrene]]
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* ] * ]


==References== == References ==
{{Reflist}} {{Reflist|30em}}

== External links ==
* {{ICSC|0104|01}}
*
* {{Cite web | title=Lung cancer as consequence by Benzopyrene in smokers | work=Lung Cancer | url=http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html | access-date=March 5, 2005 | url-status=dead | archive-url=https://web.archive.org/web/20050414175548/http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html | archive-date=April 14, 2005 }}
* {{Cite web| title=Levels of Benzopyrene in Burnt toasts| work=Guardian Unlimited, Special reports: Close encounters| url=https://www.theguardian.com/chemicalworld/story/0,14534,1219603,00.html | access-date=March 5, 2005 }}
* {{Cite journal| title=Crystal and molecular structure of a benzopyrene-7,8-diol-9,10-epoxide N2-deoxyguanosine adduct: Absolute configuration and conformation | journal=Proceedings of the National Academy of Sciences| volume=101 | doi=10.1073/pnas.0307305101 | year=2004 | last1 = Karle | first1 = I. L. | issue=6| pages=1433–8| pmid=14757823 | pmc=341736| bibcode=2004PNAS..101.1433K| doi-access=free}}<!---
* {{Cite web|title=Benzopyrene in Barbeque |work=Newhouse A1 |url=http://www.newhousenews.com/archive/seeman052004.html |accessdate=March 5, 2005 |url-status=dead |archiveurl=https://web.archive.org/web/20050216003544/http://www.newhousenews.com/archive/seeman052004.html |archivedate=February 16, 2005 }}
* {{Cite web|title=DNA interaction with Benzopyrene |work=DNA |url=http://www.mybiology.com/chime/dna_benzopyrene/dna_benzopyrene_text.htm |access-date=March 5, 2005 |url-status=dead |archive-url=https://web.archive.org/web/20041223072159/http://www.mybiology.com/chime/dna_benzopyrene/dna_benzopyrene_text.htm |archive-date=December 23, 2004 }}-->


==External links==
*{{ICSC|0104|01}}
*
*{{Cite web| title=Benzopyrene in Barbeque | work=Newhouse A1| url=http://www.newhousenews.com/archive/seeman052004.html| accessdate=March 5, 2005 }} {{Dead link|date=October 2010|bot=H3llBot}}-->
*{{Cite web| title=Lung cancer as consequence by Benzopyrene in ]rs | work=Lung Cancer| url=http://www.sarnia.com/groups/antidrug/mjmeds/mjcancr.html| accessdate=March 5, 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 | accessdate=March 5, 2005 }}
*{{Cite web| title=DNA interaction with Benzopyrene| work=DNA| url=http://www.mybiology.com/chime/dna_benzopyrene/dna_benzopyrene_text.htm| accessdate=March 5, 2005 }} {{Dead link|date=October 2010|bot=H3llBot}}
*{{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 |accessdate=January 3, 2006 }}


{{PAHs}} {{PAHs}}
{{Aryl hydrocarbon receptor modulators}}


{{DEFAULTSORT:Benzo(A)Pyrene}}
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