(+)-Benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...

with

molecular formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...

CHO. It is a metabolite and

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of benzo 'a''yrene (found in

tobacco smoke Tobacco smoke is a sooty aerosol produced by the incomplete combustion of tobacco during the smoking of cigarettes and other tobacco products. Temperatures in burning cigarettes range from about 400 °C between puffs to about 900 °C d ...

) as a result of

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

to include

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydro ...

and

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

functionalities. (+)-Benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a

guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...

nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...

in DNA, distorting the

double helix A double is a look-alike or doppelgänger; one person or being that resembles another. Double, The Double or Dubble may also refer to: Film and television * Double (filmmaking), someone who substitutes for the credited actor of a character * ...

structure by intercalation of the pyrene

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

between base pairs through π-stacking. The

carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...

ic 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 In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...

and potentially to cancer.

Structure

Pyrene is a

polycyclic aromatic hydrocarbon A polycyclic aromatic hydrocarbon (PAH) is a class of organic compounds that is composed of multiple aromatic rings. The simplest representative is naphthalene, having two aromatic rings and the three-ring compounds anthracene and phenanthrene. ...

consisting of four

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms ...

rings fused together in a planar

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

arrangement which approximates a

rhombus In plane Euclidean geometry, a rhombus (plural rhombi or rhombuses) is a quadrilateral whose four sides all have the same length. Another name is equilateral quadrilateral, since equilateral means that all of its sides are equal in length. The ...

in shape. Benzo 'a''yrene is a

in which a fifth benzene ring has been fused to the pyrene system, and is a component of

which is a

procarcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...

partly responsible for the

ic and mutagenic effects of smoking. Benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide is a metabolite of benzo 'a''yrene formed by the introduction of vicinal

and

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...

s to the fifth benzene ring. These oxidations are

stereoselective In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of ...

, 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''yrene-7,8-dihydrodiol-9,10-epoxide is specifically the (7''R'',8''S'',8a''R'',9a''S'')

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

Biosynthesis

The metabolism of the tobacco smoke procarcinogen benzo 'a''yrene 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. In the first step, a

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

1A1 (CYP1A1)

catalysed Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

oxidation produces several products including (+)-benzo 'a''yrene-7,8-epoxide. The

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

epoxide hydrolase Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...

, then

hydrates In chemistry, a hydrate is a substance that contains water or its constituent elements. The chemical state of the water varies widely between different classes of hydrates, some of which were so labeled before their chemical structure was understo ...

the

ring to yield the vicinal diol (−)-benzo 'a''yrene-7,8-dihydrodiol, which is then oxidised by

cytochrome P450 oxidase Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

again forming the mutagen and carcinogen (+)-benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide. This diol epoxide covalently binds to DNA by a ring-opening to

alkylate An alkylation unit (alky) is one of the conversion processes used in petroleum refineries. It is used to convert isobutane and low-molecular-weight alkenes (primarily a mixture of propene and butene) into alkylate, a high octane gasoline componen ...

the nucleobase forming a distorted structure, as shown at right, with intercalation of a pyrene

moiety between the base pairs favouring π-stacking; these distortions have been confirmed by X-ray crystallographic and

nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

structure studies.

Aflatoxin Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly ''Aspergillus'' species. The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, sweetcorn ...

has a similar mechanism of action, though its binding is through the N7, rather than the N2, position of guanine. Multiple

stereochemical Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

outcomes are possible from these transformations. The ''anti''

(shown here) and its enantiomer are the ultimate carcinogens from benzo 'a''yrene, but the ''syn'' isomers are also produced. :

Biochemistry

(+)-Benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide has been shown to bind to an N2 atom of a

in DNA, distorting the

structure by intercalation of the pyrene moiety between base pairs through π-stacking. There are indications that (+)-benzo 'a''yrene-7,8-dihydrodiol-9,10-epoxide specifically targets the protective

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

gene; More than 50 percent of human

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s contain a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

or deletion of the p53 gene. This gene is a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

that regulates the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...

and hence functions as a

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

. The ''anti''-benzo 'a''yrene diol epoxides induce guanine to

thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidi ...

transversion Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by i ...

s in related areas of p53, thereby inactivating its tumor suppression ability in certain cells, leading to genetic mutations and potentially to cancer. Induction of

CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 ...

by benzo 'a''yrene occurs via binding to the

aryl hydrocarbon receptor The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, or dioxin receptor) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originall ...

in the cytosol, leading the transformed receptor to translocate to the nucleus where it dimerises with

aryl hydrocarbon receptor nuclear translocator The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the be ...

and then binds xenobiotic response elements in DNA located upstream of certain genes. This process increases

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of genes including CYP1A1, resulting in increased CYP1A1 protein production. This process is similar to induction of CYP1A1 by certain

polychlorinated biphenyl Polychlorinated biphenyls (PCBs) are highly carcinogenic chemical compounds, formerly used in industrial and consumer products, whose production was banned in the United States by the Toxic Substances Control Act in 1979 and internationally by t ...

s and dioxins. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo 'a''yrene to enter portal blood and systemic circulation. Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (

TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...

), which is a eucaryotic receptor for bacterial surface structures such as

lipoteichoic acid Lipoteichoic acid (LTA) is a major constituent of the cell wall of gram-positive bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. The structure of LTA varies ...

. Moreover, benzo 'a''yrene has been found to activate a transposon, LINE1, in humans.

References

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