(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide

Cancer-causing agent derived from tobacco smoke a bracket substitution (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide.png (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (7R,8S,8aS,9aR)-7,8,8a,9a-Tetrahydrobenzo[1,12]tetrapheno[10,11-b]oxirene-7,8-diol (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide(+)-7,8,9,10-Tetrahydrobenzo[a]pyrene-7,8-diol-9,10-epoxide(7R,8S,8aR,9aS)-7,8,8a,9a-Tetrahydrobenzo[1,12]tetrapheno[10,11-b]oxirene-7,8-diol7,8,8a,9a-Tetrahydro-(7R,8S,8aR,9aS)-benzo[10,11]chryseno[3,4-b]oxirene-7,8-diol 40465 42879 correct FDA 8942B964DU 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 DQEPMTIXHXSFOR-FUMNGEBKSA-N correct CAS 58917-91-2 O[C@@H]3c1cc4ccc5cccc6ccc(c1[C@H]2O[C@H]2[C@H]3O)c4c56 20 14 3 1.6 ± 0.1 g cm−3 594.2 ± 50.0 °C at 760 mmHg Soluble in dimethyl sulfoxide, dichloromethane, methanol (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer. Structure left|thumb|250px|Space-filling model of pyrene showing the planar structure Pyrene is a polycyclic aromatic hydrocarbon consisting of four benzene rings fused together in a planar aromatic arrangement which approximates a rhombus in shape. Benzo[a]pyrene is a derivative in which a fifth benzene ring has been fused to the pyrene system, and is a component of tobacco smoke which is a procarcinogen partly responsible for the carcinogenic and mutagenic effects of smoking. Properties and Uses of Aromatic Compounds 65–66 https://books.google.com/books?id=sawWAAAAQBAJ&q=aromatic+biochemistry&pg=PA65 Organic and Biochemistry for Today S. L. Seager M. R. Slabaugh Cengage Learning 2013 978-1-285-60590-6 8th Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is a metabolite of benzo[a]pyrene formed by the introduction of vicinal hydroxyl and epoxide functional groups to the fifth benzene ring. These oxidations are stereoselective, producing the pair of enantiomers 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 (7R,8S,8aR,9aS) stereoisomer. Biosynthesis The metabolism of the tobacco smoke procarcinogen benzo[a]pyrene involves three distinct steps – the introduction of an epoxide group in the 7,8-position, its hydration to a vicinal diol and the introduction of an epoxide in the 9,10-position. Jiang H. Gelhaus S. L. Mangal D. Harvey R. G. Blair I. A. Penning T. M. 2007 Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography-Mass Spectrometry Chemical Research in Toxicology 20 9 1331–1341 17702526 10.1021/tx700107z 2423818 Uno S. Dalton T. P. Dragin N. Curran C. P. Derkenne S. Miller M. L. Shertzer H. G. Gonzalez F. J. Nebert D. W. 2006 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 Molecular Pharmacology 69 4 1103–1112 16377763 10.1124/mol.105.021501 10834208 In the first step, a cytochrome P450 1A1 (CYP1A1) catalysed oxidation produces several products including (+)-benzo[a]pyrene-7,8-epoxide. Shou M. Gonzalez F. J. Harry Gelboin Gelboin H. V. 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 15807–15813 10.1021/bi962042z 8961944 The enzyme epoxide hydrolase, then hydrates the epoxide ring to yield the vicinal diol (−)-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 alkylate the nucleobase forming a distorted structure, as shown at right, with intercalation of a pyrene polycyclic aromatic hydrocarbon moiety between the base pairs favouring π-stacking; these distortions have been confirmed by X-ray crystallographic and nuclear magnetic resonance structure studies. Solution Structure of a Trans-Opened (10S)-dA Adduct of (+)-(7S,8R,9S,10R)-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 Pradhan P. Tirumala S. Liu X. Sayer J. M. Jerina D. M. Yeh H. J. C. 2001 Biochemistry 40 20 5870–5881 11352722 10.1021/bi002896q Aflatoxin has a similar mechanism of action, though its binding is through the N7, rather than the N2, position of guanine. Eaton D. L. Gallagher E. P. Mechanisms of Aflatoxin Carcinogenesis Annual Review of Pharmacology and Toxicology 1994 34 135–172 8042848 10.1146/annurev.pa.34.040194.001031 Multiple stereochemical outcomes are possible from these transformations. The anti stereoisomer (shown here) and its enantiomer are the ultimate carcinogens from benzo[a]pyrene, but the syn isomers are also produced. https://books.google.com/books?id=Fw_G7Sk382IC&q=Benzo%28a%29pyrene+stereochemistry&pg=PA99 W. Kleiböhmer Elsevier 2001 Polycyclic Aromatic Hydrocarbon (PAH) Metabolites 99–122 Environmental Analysis (Volume 3 of Handbook of Analytical Separations) 978-0-08-050576-3 800px Biochemistry right|thumb|250px|A 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 guanine nucleobase in DNA, Crystal and Molecular Structure of a Benzo[a]pyrene-7,8-diol-9,10-epoxide N2-Deoxyguanosine Adduct: Absolute Configuration and Conformation I. L. Karle H. Yagi J. M. Sayer D. M. Jerina Proceedings of the National Academy of Sciences of the United States of America 2004 101 6 1433–1438 10.1073/pnas.0307305101 14757823 341736 2004PNAS..101.1433K free distorting the double helix structure Volk D. E. Thiviyanathan V. Rice J. S. Luxon B. A. Shah J. H. Yagi H. Sayer J. M. Yeh H. J. Jerina D. M. Gorenstein D. G. Solution structure of a cis-opened (10R)-N6-deoxyadenosine adduct of (9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in a DNA duplex Biochemistry 2003 42 6 1410–1420 10.1021/bi026745u 12578353 by intercalation of the pyrene moiety between base pairs through π-stacking. Noncovalent Interactions of a Benzo[a]pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-BaP DE-2 with DNA J. C. Hargis H. F. Schaefer K. N. Houk S. E. Wheeler Journal of Physical Chemistry A 2010 114 4 2038–2044 10.1021/jp911376p 2826197 20063873 2010JPCA..114.2038H There are indications that (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide specifically targets the protective p53 gene; Pfeifer G. P. Denissenko M. F. Olivier M. Tretyakova N. Hecht S. S. Hainaut P. Tobacco Smoke Carcinogens, DNA Damage and p53 Mutations in Smoking-Associated Cancers Oncogene 2002 21 48 7435–7451 12379884 10.1038/sj.onc.1205803 free More than 50 percent of human tumors contain a mutation or deletion of the p53 gene. Hollstein M. Sidransky D. Vogelstein B. Harris C. C. p53 Mutations in Human Cancers Science 253 5015 49–53 1991 1905840 10.1126/science.1905840 1991Sci...253...49H 38527914 https://zenodo.org/record/1230948 This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. The anti-benzo[a]pyrene diol epoxides induce guanine to thymine transversions in related areas of p53, thereby inactivating its tumor suppression ability in certain cells, leading to genetic mutations and potentially to cancer. Carcinogenic Epoxides of Benzo[a]pyrene and Cyclopenta[cd]pyrene Induce Base Substitutions via Specific Transversions E. Eisenstadt A. J. Warren J. Porter D. Atkins J. H. Miller Proceedings of the National Academy of Sciences of the United States of America 1982 79 6 1945–1949 7043469 346098 10.1073/pnas.79.6.1945 1982PNAS...79.1945E free Induction of CYP1A1 by benzo[a]pyrene occurs via binding to the aryl hydrocarbon receptor in the cytosol, leading the transformed receptor to translocate to the nucleus where it dimerises with 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. Whitlock J. P. Induction of Cytochrome P4501A1 Annual Review of Pharmacology and Toxicology 39 103–125 1999 10.1146/annurev.pharmtox.39.1.103 10331078 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. Uno S. Dragin N. Miller M. L. Dalton T. P. F. J. Gonzalez Nebert D. W. 2008 Basal and Inducible CYP1 mRNA Quantitation and Protein Localization throughout the Mouse Gastrointestinal Tract Free Radical Biology and Medicine 44 4 570–583 17997381 10.1016/j.freeradbiomed.2007.10.044 2754765 Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2), Do K. N. Fink L. N. Jensen T. E. Gautier L. Parlesak A. 2012 TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1 PLoS ONE 7 3 e32309 10.1371/journal.pone.0032309 22442665 3307708 2012PLoSO...732309D free which is a eucaryotic receptor for bacterial surface structures such as lipoteichoic acid. Moreover, benzo[a]pyrene has been found to activate a transposon, LINE1, in humans. Stribinskis V. Ramos K. S. 2006 Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo[a]pyrene, a Ubiquitous Environmental Carcinogen Cancer Research 66 5 2616–2620 16510580 10.1158/0008-5472.can-05-3478 free References Category:Human metabolites Category:Epoxides Category:Vicinal diols Category:Pyrenes