View source for Chemistry:(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide

{{short description|Cancer-causing agent derived from tobacco smoke}}
{{DISPLAYTITLE:(+)-Benzo(''a'')pyrene-7,8-dihydrodiol-9,10-epoxide}}
{{chembox
| Watchedfields = 
| verifiedrevid =
| Name =(+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide
| ImageFile =(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide.png
| ImageSize = 
| ImageFile1 =
| ImageSize1 = 
| ImageName =(+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide
| PIN = (7''R'',8''S'',8a''S'',9a''R'')-7,8,8a,9a-Tetrahydrobenzo[1,12]tetrapheno[10,11-''b'']oxirene-7,8-diol
| OtherNames = (+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide<br>(+)-7,8,9,10-Tetrahydrobenzo[''a'']pyrene-7,8-diol-9,10-epoxide<br>(7''R'',8''S'',8a''R'',9a''S'')-7,8,8a,9a-Tetrahydrobenzo[1,12]tetrapheno[10,11-b]oxirene-7,8-diol<br>7,8,8a,9a-Tetrahydro-(7''R'',8''S'',8a''R'',9a''S'')-benzo[10,11]chryseno[3,4-''b'']oxirene-7,8-diol
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref =
| ChemSpiderID =40465
| PubChem = 42879
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8942B964DU
| KEGG_Ref =
| KEGG =
| InChI =
| InChIKey =
| ChEMBL_Ref =
| ChEMBL =
| StdInChI_Ref =
| StdInChI =1S/C20H14O3/c21-17-13-8-11-5-4-9-2-1-3-10-6-7-12(15(11)14(9)10)16(13)19-20(23-19)18(17)22/h1-8,17-22H/t17-,18+,19+,20-/m1/s1
| StdInChIKey_Ref =
| StdInChIKey =DQEPMTIXHXSFOR-FUMNGEBKSA-N 
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 58917-91-2
| ChEBI_Ref =
| ChEBI =
| SMILES = O[C@@H]3c1cc4ccc5cccc6ccc(c1[C@H]2O[C@H]2[C@H]3O)c4c56}}
|Section2={{Chembox Properties
| C=20 | H=14 | O=3
| Density = 1.6&nbsp;±&nbsp;0.1&nbsp;g&nbsp;cm{{sup|&minus;3}} 
| MeltingPtC =
| MeltingPt_notes = 
| BoilingPt =594.2&nbsp;±&nbsp;50.0&nbsp;°C at 760&nbsp;mmHg
| BoilingPt_notes = 
| Solubility =[[Chemistry:Dimethyl sulfoxide|Dimethyl sulfoxide]], [[Chemistry:Dichloromethane|dichloromethane]], [[Chemistry:Methanol|methanol]]}}
}}

'''(+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide''' is an [[Chemistry:Organic compound|organic compound]] with molecular formula C{{sub|20}}H{{sub|14}}O{{sub|3}}.  It is a [[Biology:Metabolite|metabolite]] and [[Chemistry:Derivative|derivative]] of [[Chemistry:Benzo(a)pyrene|benzo[''a'']pyrene]] (found in [[Chemistry:Tobacco smoke|tobacco smoke]]<ref name = derivative />) as a result of oxidation to include hydroxyl and [[Chemistry:Epoxide|epoxide]] functionalities.  (+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a [[Chemistry:Guanine|guanine]] [[Biology:Nucleobase|nucleobase]] in [[Biology:DNA|DNA]],<ref name = DNAbound /><ref name = N2 /> distorting the double helix structure<ref name = distortion /> by [[Chemistry:Intercalation (biochemistry)|intercalation]] of the [[Chemistry:Pyrene|pyrene]] [[Chemistry:Moiety|moiety]] between base pairs through [[Chemistry:Stacking|π-stacking]].<ref name = pi-stacking />  The [[Biology:Carcinogen|carcinogen]]ic properties of tobacco smoking are attributed in part to this compound binding and inactivating the [[Biology:P53|tumor suppression ability]] of certain genes, leading to [[Physics:Mutagen|genetic mutations]] and potentially to cancer.<ref name = cancer />

== Structure ==
[[Image:Pyrene 3D spacefill.png|left|thumb|250px|[[Space-filling model|Space-filling model]] of pyrene showing the planar structure]]<!--this doesn't look like the ones in the "pyrene" article; the ring structure seems different-->
[[Chemistry:Pyrene|Pyrene]] is a [[Astronomy:Polycyclic aromatic hydrocarbon|polycyclic aromatic hydrocarbon]] consisting of four [[Chemistry:Benzene|benzene]] rings fused together in a planar [[Chemistry:Aromaticity|aromatic]] arrangement which approximates a [[Rhombus|rhombus]] in shape.  [[Chemistry:Benzo(a)pyrene|Benzo[''a'']pyrene]] is a [[Chemistry:Derivative|derivative]] in which a fifth benzene ring has been fused to the pyrene system, and is a component of [[Chemistry:Tobacco smoke|tobacco smoke]] which is a procarcinogen partly responsible for the [[Biology:Carcinogen|carcinogen]]ic and [[Physics:Mutagen|mutagen]]ic effects of smoking.<ref name = derivative>{{cite book|chapter = Properties and Uses of Aromatic Compounds|pages = 65–66|chapter-url = https://books.google.com/books?id=sawWAAAAQBAJ&q=aromatic+biochemistry&pg=PA65|title = Organic and Biochemistry for Today|first1 = S. L.|last1 = Seager|first2 = M. R.|last2 = Slabaugh|publisher = Cengage Learning|year = 2013|isbn = 9781285605906|edition = 8th}}</ref>  Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide is a [[Biology:Metabolite|metabolite]] of benzo[''a'']pyrene formed by the introduction of [[Chemistry:Vicinal|vicinal]] hydroxyl and [[Chemistry:Epoxide|epoxide]] [[Chemistry:Functional group|functional group]]s to the fifth benzene ring.<ref name = epoxidation />  These oxidations are stereoselective, producing the pair of [[Chemistry:Enantiomer|enantiomer]]s with the hydroxyl groups on opposite sides of the pyrene plane and with the epoxide on the same side as its adjacent hydroxyl group.   (+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide is specifically the (7''R'',8''S'',8a''R'',9a''S'') stereoisomer.

=== Biosynthesis ===  
The metabolism of the tobacco smoke procarcinogen benzo[''a'']pyrene involves three distinct steps &ndash; the introduction of an epoxide group in the 7,8-position, its [[Chemistry:Hydrolysis|hydration]] to a vicinal [[Chemistry:Diol|diol]] and the introduction of an epoxide in the 9,10-position.<ref>{{cite journal|last1 = Jiang|first1 = H.|last2 = Gelhaus|first2 = S. L.|last3 = Mangal|first3 = D.|last4 = Harvey|first4 = R. G.|last5 = Blair|first5 = I. A.|last6 = Penning|first6 = T. M.|year = 2007|title = Metabolism of Benzo[''a'']pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry|journal = [[Chemistry:Chemical Research in Toxicology|Chemical Research in Toxicology]]|volume = 20|issue = 9|pages = 1331–1341|pmid = 17702526|doi = 10.1021/tx700107z|pmc=2423818}}</ref><ref>{{cite journal|last1 = Uno|first1 = S.|last2 = Dalton|first2 = T. P.|last3 = Dragin|first3 = N.|last4 = Curran|first4 = C. P.|last5 = Derkenne|first5 = S.|last6 = Miller|first6 = M. L.|last7 = Shertzer|first7 = H. G.|last8 = Gonzalez|first8 = F. J.|last9 = Nebert|first9 = D. W.|year = 2006|title = Oral Benzo[''a'']pyrene in Cyp1 Knockout Mouse Lines: CYP1A1 Important in Detoxication, CYP1B1 Metabolism Required for Immune Damage Independent of Total-Body Burden and Clearance Rate|journal = Molecular Pharmacology|volume = 69|issue = 4|pages = 1103–1112|pmid = 16377763|doi = 10.1124/mol.105.021501|s2cid = 10834208}}</ref>  In the first step, a [[Biology:Cytochrome P450|cytochrome P450]] [[Biology:Cytochrome P450, family 1, member A1|1A1]] (CYP1A1) [[Chemistry:Catalyst|catalysed]] oxidation produces several products including (+)-benzo[''a'']pyrene-7,8-epoxide.<ref name = epoxidation>{{cite journal|last1 = Shou|first1 = M.|last2 = Gonzalez|first2 = F. J. |last3 = Gelboin|first3 = H. V.|year = 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 = 15807–15813|doi=10.1021/bi962042z|pmid=8961944}}</ref>  The [[Biology:Enzyme|enzyme]] [[Biology:Epoxide hydrolase|epoxide hydrolase]], then hydrates the [[Chemistry:Epoxide|epoxide]] ring to yield the vicinal diol (&minus;)-benzo[''a'']pyrene-7,8-dihydrodiol, which is then oxidised by cytochrome P450 oxidase again forming the mutagen and carcinogen (+)-benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide.  This diol epoxide covalently binds to DNA by a ring-opening to [[Chemistry:Alkylation|alkylate]] the nucleobase forming a distorted structure, as shown at right, with [[Chemistry:Intercalation (biochemistry)|intercalation]] of a [[Chemistry:Pyrene|pyrene]] [[Astronomy:Polycyclic aromatic hydrocarbon|polycyclic aromatic hydrocarbon]] moiety between the base pairs favouring π-stacking;<ref name = pi-stacking /> these distortions have been confirmed by [[Physics:X-ray crystallography|X-ray crystallographic]] and [[Physics:Nuclear magnetic resonance|nuclear magnetic resonance]] structure studies.<ref name = DNAbound>{{cite journal|title = Solution Structure of a Trans-Opened (10''S'')-dA Adduct of (+)-(7''S'',8''R'',9''S'',10''R'')-7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[''a'']pyrene in a fully Complementary DNA Duplex: Evidence for a Major ''Syn'' Conformation|last1 = Pradhan|first1 = P.|last2 = Tirumala|first2 = S.|last3 = Liu|first3 = X.|last4 = Sayer|first4 = J. M.|last5 = Jerina|first5 = D. M.|last6 = Yeh|first6 = H. J. C.|year = 2001|journal = Biochemistry|volume = 40|issue = 20|pages = 5870–5881|pmid = 11352722|doi = 10.1021/bi002896q}}</ref>  [[Chemistry:Aflatoxin|Aflatoxin]] has a similar mechanism of action, though its binding is through the N7, rather than the N2,<ref name = N2 /> position of guanine.<ref>{{cite journal|last1 = Eaton|first1 = D. L.|last2 = Gallagher|first2 = E. P.|title = Mechanisms of Aflatoxin Carcinogenesis|journal = Annual Review of Pharmacology and Toxicology|year = 1994|volume = 34|pages = 135–172|pmid = 8042848|doi = 10.1146/annurev.pa.34.040194.001031}}</ref>  Multiple [[Chemistry:Stereochemistry|stereochemical]] outcomes are possible from these transformations.  The [[Chemistry:Syn and anti addition|''anti'']] stereoisomer (shown here) and its [[Chemistry:Enantiomer|enantiomer]] are the ultimate carcinogens from benzo[''a'']pyrene, but the ''syn'' isomers are also produced.<ref>{{cite book|chapter-url = https://books.google.com/books?id=Fw_G7Sk382IC&q=Benzo%28a%29pyrene+stereochemistry&pg=PA99|first = W.|last = Kleiböhmer|publisher = [[Company:Elsevier|Elsevier]]|year = 2001|chapter = Polycyclic Aromatic Hydrocarbon (PAH) Metabolites|pages = 99–122|title = Environmental Analysis (Volume 3 of Handbook of Analytical Separations)|isbn = 9780080505763}}</ref>
:[[Image:Benzo(a)pyrene metabolism.svg|800px]]

== Biochemistry ==
[[File:Benzopyrene DNA adduct 1JDG.png|right|thumb|250px|A [[Medicine:DNA adduct|DNA adduct]] (at center) of a metabolite of benzo[''a'']pyrene.]]
(+)-Benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide has been shown to bind to an N2 atom of a [[Chemistry:Guanine|guanine]] [[Biology:Nucleobase|nucleobase]] in [[Biology:DNA|DNA]],<ref name = DNAbound /><ref name = N2>{{cite journal|title = Crystal and Molecular Structure of a Benzo[''a'']pyrene-7,8-diol-9,10-epoxide N{{sup|2}}-Deoxyguanosine Adduct: Absolute Configuration and Conformation|first1 = I. L.|last1 = Karle|first2 = H.|last2 = Yagi|first3 = J. M.|last3 = Sayer|first4 = D. M.|last4 = Jerina|journal = Proceedings of the National Academy of Sciences of the United States of America|year = 2004|volume = 101|issue = 6|pages = 1433–1438|doi = 10.1073/pnas.0307305101|pmid = 14757823|pmc=341736|bibcode = 2004PNAS..101.1433K|doi-access = free}}</ref> distorting the double helix structure<ref name = distortion>{{cite journal|last1 = Volk|first1 = D. E.|last2 = Thiviyanathan|first2 = V.|last3 = Rice|first3 = J. S.|last4 = Luxon|first4 = B. A.|last5 = Shah|first5 = J. H.|last6 = Yagi|first6 = H.|last7 = Sayer|first7 = J. M.|last8 = Yeh|first8 = H. J.|last9 = Jerina|first9 = D. M.|last10 = Gorenstein|first10 = D. G.|title = Solution structure of a ''cis''-opened (10''R'')-N{{sup|6}}-deoxyadenosine adduct of (9''S'',10''R'')-9,10-epoxy-7,8,9,10-tetrahydrobenzo[''a'']pyrene in a DNA duplex|journal = Biochemistry|year = 2003|volume = 42|issue = 6|pages = 1410–1420|doi = 10.1021/bi026745u|pmid = 12578353}}</ref> by [[Chemistry:Intercalation (biochemistry)|intercalation]] of the pyrene moiety between base pairs through [[Chemistry:Stacking|π-stacking]].<ref name = pi-stacking>{{cite journal|title = Noncovalent Interactions of a Benzo[''a'']pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-B''a''P DE-2 with DNA|first1 = J. C.|last1 = Hargis|first2 = H. F.|last2 = Schaefer|first3 =  K. N.|last3 = Houk|first4 = S. E.|last4 = Wheeler|journal = Journal of Physical Chemistry A|year = 2010|volume = 114|issue = 4|pages = 2038–2044|doi = 10.1021/jp911376p|pmc = 2826197|pmid=20063873|bibcode = 2010JPCA..114.2038H}}</ref>

There are indications that (+)-benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide specifically targets the protective [[Biology:P53|p53]] gene;<ref>{{cite journal|last1 = Pfeifer|first1 = G. P.|last2 = Denissenko|first2 = M. F.|last3 = Olivier|first3 = M.|last4 = Tretyakova|first4 = N.|last5 = Hecht|first5 = S. S.|last6 = Hainaut|first6 = P.|title = Tobacco Smoke Carcinogens, DNA Damage and p53 Mutations in Smoking-Associated Cancers|journal = Oncogene|year = 2002|volume = 21|issue = 48|pages = 7435–7451|pmid = 12379884|doi = 10.1038/sj.onc.1205803|doi-access = free}}</ref> More than 50 percent of human tumors contain a [[Biology:Mutation|mutation]] or deletion of the p53 gene.<ref>{{cite journal|last1 = Hollstein|first1 = M.|last2 = Sidransky|first2 = D.|last3 = Vogelstein|first3 = B.|last4 = Harris|first4 = C. C.|title = p53 Mutations in Human Cancers|journal = Science|volume = 253|issue = 5015|pages = 49–53|year = 1991|pmid = 1905840|doi = 10.1126/science.1905840|bibcode = 1991Sci...253...49H| s2cid=38527914 |url = https://zenodo.org/record/1230948}}</ref>  This gene is a [[Biology:Transcription factor|transcription factor]] that regulates the [[Biology:Cell cycle|cell cycle]] and hence functions as a [[Biology:Tumor suppressor|tumor suppressor]]. The ''anti''-benzo[''a'']pyrene diol epoxides induce guanine to [[Chemistry:Thymine|thymine]] [[Biology:Transversion|transversion]]s in related areas of p53, thereby inactivating its tumor suppression ability in certain cells, leading to genetic mutations and potentially to cancer.<ref name = cancer>{{cite journal|title = Carcinogenic Epoxides of Benzo[''a'']pyrene and Cyclopenta[''cd'']pyrene Induce Base Substitutions via Specific Transversions|first1 = E.|last1 = Eisenstadt|first2 = A. J.|last2 = Warren|first3 = J.|last3 = Porter|first4 = D.|last4 = Atkins|first5 = J. H.|last5 = Miller|journal = Proceedings of the National Academy of Sciences of the United States of America|year = 1982|volume = 79|issue = 6|pages = 1945–1949|pmid = 7043469|pmc = 346098|doi = 10.1073/pnas.79.6.1945|bibcode = 1982PNAS...79.1945E|doi-access = free}}</ref>

Induction of [[Biology:CYP1A1|CYP1A1]] by benzo[''a'']pyrene occurs via binding to the [[Biology:Aryl hydrocarbon receptor|aryl hydrocarbon receptor]] in the cytosol, leading the transformed receptor to translocate to the nucleus where it [[Chemistry:Dimer|dimerises]] with [[Biology:Aryl hydrocarbon receptor nuclear translocator|aryl hydrocarbon receptor nuclear translocator]] and then binds xenobiotic response elements in DNA located upstream of certain genes.  This process increases transcription of genes including CYP1A1, resulting in increased CYP1A1 protein production.<ref>{{cite journal|last = Whitlock|first = J. P.|title = Induction of Cytochrome P4501A1|journal = Annual Review of Pharmacology and Toxicology|volume = 39|pages = 103–125|year = 1999|doi = 10.1146/annurev.pharmtox.39.1.103|pmid = 10331078}}</ref> This process is similar to induction of CYP1A1 by certain [[Chemistry:Polychlorinated biphenyl|polychlorinated biphenyl]]s and [[Chemistry:Polychlorinated dibenzodioxins|dioxins]]. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo[''a'']pyrene to enter portal blood and systemic circulation.<ref>{{cite journal|last1 = Uno|first1 = S.|last2 = Dragin|first2 = N.|last3 = Miller|first3 = M. L.|last4 = Dalton|first4 = T. P.|first5 = F. J.|last5 = Gonzalez|last6 = Nebert|first6 = D. W.|year = 2008|title = Basal and Inducible CYP1 mRNA Quantitation and Protein Localization throughout the Mouse Gastrointestinal Tract|journal = [[Medicine:Free Radical Biology and Medicine|Free Radical Biology and Medicine]]|volume = 44|issue = 4|pages = 570–583|pmid = 17997381|doi = 10.1016/j.freeradbiomed.2007.10.044|pmc=2754765}}</ref> Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 ([[Biology:TLR2|TLR2]]),<ref>{{cite journal|last1 = Do|first1 = K. N.|last2 = Fink|first2 = L. N.|last3 = Jensen|first3 = T. E.|last4 = Gautier|first4 = L.|last5 = Parlesak|first5 = A.|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 eucaryotic receptor for bacterial surface structures such as [[Biology:Lipoteichoic acid|lipoteichoic acid]]. Moreover, benzo[''a'']pyrene has been found to activate a transposon, [[Biology:Retrotransposon|LINE1]], in humans.<ref>{{cite journal|last1 = Stribinskis|first1 = V.|last2 = Ramos|first2 = K. S.|year = 2006|title = Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo[''a'']pyrene, a Ubiquitous Environmental Carcinogen|journal = Cancer Research|volume = 66|issue = 5|pages = 2616–2620|pmid = 16510580|doi = 10.1158/0008-5472.can-05-3478|doi-access = free}}</ref>

==References==

{{Reflist}}

{{DEFAULTSORT:Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide, (+)-}}
[[Category:Human metabolites]]
[[Category:Epoxides]]
[[Category:Vicinal diols]]
[[Category:Pyrenes]]

{{Sourceattribution|(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide}}