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

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The correct title of this article is (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. The substitution or omission of any brackets is due to technical restrictions.
(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide
(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide
Names
IUPAC name
(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide
Identifiers
Properties
C20H15O3
Molar mass 303.337 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is a polycyclic aromatic hydrocarbon derivative of pyrene which has been oxidised to include hydroxyl and epoxide funcationalities. It is the metabolite of benzo[a]pyrene, which is a component of tobacco smoke, and it is partly responsible for the carcinogenic and mutagenic effects of smoking.[1] (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide has been shown to bind to an N2 atom of a guanine nucleobase in DNA,[2] distorting the double helix structure[3] by intercalation of the pyrene moiety between base pairs through π-stacking.

A DNA adduct (at center) of a metabolite of benzo[a]pyrene.

The metabolism of benzo[a]pyrene (technically a procarcinogen) involves the sequential oxidation of the aromatic system to produce an epoxide and a vicinal diol:[4]

  1. Benzo[a]pyrene is first oxidized by cytochrome P450 1A1 (CYP1A1) to form a variety of products, including (+)-benzo[a]pyrene-7,8-epoxide.[5]
  2. This product is metabolized by epoxide hydrolase, hydrating the epoxide ring to yield the vicinal diol (-)-benzo[a]pyrene-7,8-dihydrodiol.
  3. The ultimate mutagen and carcinogen is formed after another reaction with cytochrome P450 oxidase to yield the (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide.

This diol epoxide covalently binds to DNA by a ring-opening to alkylate the nucleobase to form a distorted structure, as shown at right, producing mutagenic effects; these distortions have been confirmed by X-ray crystallographic and nuclear magnetic resonance structure studies.[2] Aflatoxin has a similar mechanism of action, though its binding is through the N7, rather than the N2, position of guanine.[6]

There are indications that (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide specifically targets the protective p53 gene.[7] 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 induces CYP1A1 by binding to the aryl hydrocarbon receptor in the cytosol Upon binding the transformed receptor translocates 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 certain genes, notably CYP1A1, followed by increased CYP1A1 protein production..[8] 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.[9] Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2),[10] 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.[11]

Refernces

  1. ^ Seager, S. L.; Slabaugh, M. R. (2013). "Properties and Uses of Aromatic Compounds". Organic and Biochemistry for Today (8th ed.). Cengage Learning. pp. 65–66. ISBN 9781285605906.
  2. ^ a b Pradhan, P.; Tirumala, S.; Liu, X.; Sayer, J. M.; Jerina, D. M.; Yeh, H. J. C. (2001). "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". Biochemistry. 40 (20): 5870–5881. doi:10.1021/bi002896q. PMID 11352722.
  3. ^ 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. (2003). "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.
  4. ^ 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. doi:10.1021/tx700107z. PMID 17702526.
  5. ^ Shou, M.; Gonzalez, F. J.; 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. doi:10.1021/bi962042z. PMID 8961944.
  6. ^ 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.
  7. ^ Pfeifer, G. P.; Denissenko, M. F.; Olivier, M.; Tretyakova, N.; Hecht, S. S.; Hainaut, P. (2002). "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.
  8. ^ Whitlock, J. P. (1999). "Induction of Cytochrome P4501A1". Annual Review of Pharmacology and Toxicology. 39: 103–125. doi:10.1146/annurev.pharmtox.39.1.103. PMID 10331078.
  9. ^ Uno, S.; Dragin, N.; Miller, M. L.; Dalton, T. P. (2008). "Basal and Inducible CYP1 mRNA Quantitation and Protein Localization throughout the Mouse Gastrointestinal Tract". Free Radical Biology and Medicine. 44 (4): 570–583. doi:10.1016/j.freeradbiomed.2007.10.044. PMID 17997381.
  10. ^ Do, K. N.; Fink, L. N.; Jensen, T. E.; Gautier, L.; Parlesak, A. (2012). "TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1". Public Library of Science ONE. 7 (3): e32309. doi:10.1371/journal.pone.0032309. PMID 22442665.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ 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. PMID 16510580.
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