Benzo[a]pyrene (BaP orB[a]P) is apolycyclic aromatic hydrocarbon and the result of incomplete combustion oforganic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of thebenzopyrenes, formed by abenzene ring fused topyrene. Itsdiolepoxide metabolites, more commonly known as BPDE, react with and bind toDNA, resulting in mutations and eventually cancer. It is listed as aGroup 1 carcinogen by theIARC. In the 18th century a scrotal cancer of chimney sweepers, thechimney sweeps' carcinoma, was already known to be connected to soot.
Benzo[a]pyrene (BaP) is apolycyclic aromatic hydrocarbon found incoal tar with the formula C20H12. The compound is one of thebenzopyrenes, formed by abenzene ring fused topyrene, and is the result of incomplete combustion at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F).
The main source of atmospheric BaP is residential wood burning.[4] It is also found incoal tar, inautomobile exhaust fumes (especially fromdiesel engines), in all smoke resulting from the combustion of organic material (includingcigarette smoke), and incharbroiled food.A 2001National Cancer Institute study found levels of BaP to be significantly higher in foods that were cooked well-done on thebarbecue, particularlysteaks,chicken with skin, andhamburgers: Cooked meat products have been shown to contain up to 4 ng/g of BaP,[5] and up to 5.5 ng/g in fried chicken[6] and 62.6 ng/g in overcooked charcoal barbecued beef.[7]
In the 18th century, young Britishchimney sweeps who climbed into chimneys suffered fromchimney sweeps' carcinoma, a scrotal cancer peculiar to their profession, and this was connected to the effects ofsoot in 1775,[10] in the first work ofoccupational cancer epidemiology and also the first connection of anychemical mixture to cancer formation. Frequentskin cancers were noted among fuel industry workers in the 19th century. In 1933, BaP 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.[11] BaP has since been identified as a prime carcinogen in cigarette smoke.[12]
Prenatal exposure of BaP in rats is known to affect learning and memory in rodent models. Pregnant rats eating BaP were shown to negatively affect the brain function in the late life of their offspring. At a time whensynapses are first formed and adjusted in strength by activity, BaP diminishedNMDA receptor-dependent nerve cell activity measured as mRNA expression of the NMDANR2B receptor subunit.[13]
BaP has an effect on the number ofwhite blood cells, inhibiting some of them from differentiating intomacrophages, 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 immunoreceptorsCD32 (a member of the Fc family of immunoreceptors) could bind toIgG and turn the white blood cell into a macrophage. Therefore, macrophage membranes become susceptible to bacterial infections.[14]
In experiments with male rats,subchronic exposure to inhaled BaP has been shown to generally reduce the function of testicles andepididymis with lower sex steroid/testosterone production and sperm production.[15]
BaP's metabolites aremutagenic and highlycarcinogenic, and it is listed as aGroup 1 carcinogen by theIARC. Chemical agents and related occupations, Volume 10, A review of Human Carcinogens, IARC Monographs, Lyon France 2009[16]
Numerous studies since the 1970s have documented links between BaP and cancers.[18] It has been more difficult to link cancers to specific BaP sources, especially in humans, and difficult to quantify risks posed by various methods of exposure (inhalation or ingestion).[19] A link betweenvitamin A deficiency andemphysema insmokers was described in 2005 to be due to BaP, which induces vitamin A deficiency in rats.[20]
A 1996 study provided molecular evidence linking components intobacco smoke tolung cancer. BaP was shown to cause genetic damage in lung cells that was identical to the damage observed in theDNA of most malignantlung tumours.[21]
Regular consumption ofcooked meats has been epidemiologically associated with increased levels ofcolon cancer[22] (although this in itself does notprove carcinogenicity),[23]A 2005 NCI study found an increased risk ofcolorectal adenomas was associated with BaP intake, and more strongly with BaP intake from all foods.[24]
The detoxification enzymes cytochrome P4501A1 (CYP1A1) and cytochrome P4501B1 (CYP1B1) are both protective and necessary for benzo[a]pyrene toxicity. Experiments with strains of mice engineered to remove (knockout) CYP1A1 and CYP1B1 reveal that CYP1A1 primarily acts to protect mammals from low doses of BaP, and that removing this protection accumulates large concentrations of BaP. Unless CYP1B1 is also knocked out, toxicity results from thebioactivation of BaP to benzo[a]pyrene -7,8-dihydrodiol-9,10-epoxide, the ultimate toxic compound.[25][better source needed]
Properly speaking, BaP is aprocarcinogen, meaning that its mechanism ofcarcinogenesis depends on its enzymatic metabolism to BaPdiolepoxide[27] Itintercalates inDNA, and the electrophilic epoxide is attacked by nucleophilicguanine bases, forming a bulky guanine adduct.[27]
X-ray crystallographic andnuclear magnetic resonance structure studies have shown how this binding distorts the DNA[28] by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence ofcancer after exposure. This mechanism of action is similar to that ofaflatoxin which binds to the N7 position of guanine.[29]
There are indications that benzo[a]pyrene diol epoxide specifically targets the protectivep53 gene.[30] This gene is atranscription factor that regulates thecell cycle and hence functions as atumor suppressor. By inducing G (guanine) to T (thymidine)transversions in transversion hotspots withinp53, there is a probability that benzo[a]pyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.
Benzo[a]pyrene is first oxidized bycytochrome P4501A1 to form a variety of products, including (+)benzo[a]pyrene-7,8-epoxide.[32]
This product is metabolized byepoxide hydrolase, opening up theepoxide ring to yield (−)benzo[a]pyrene-7,8-dihydrodiol.
The ultimate carcinogen is formed after another reaction withcytochrome P450 1A1 to yield the (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.
BaP induces cytochrome P450 1A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol.[33] Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) and then bindsxenobiotic response elements (XREs) in DNA located upstream of certain genes. This process increasestranscription of certain genes, notablyCYP1A1, followed by increased CYP1A1 protein production.[33] This process is similar to induction of CYP1A1 by certainpolychlorinated biphenyls anddioxins. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo[a]pyrene to enter portal blood and systemic circulation.[34] Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2),[35] which is a eukaryotic receptor for bacterial surface structures such aslipoteichoic acid.
Moreover, BaP has been found to activate a transposon,LINE1, in humans.[36]
As illustrated above, (+)benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) forms bulky covalentDNA adducts withguanines. Most of these adducts can be efficiently eliminated from DNA by the process ofnucleotide excision repair.[37] Those adducts that are not removed can cause errors duringDNA replication leading to carcinogenicmutations.
^Lee, BM; Shim, GA (Aug 2007). "Dietary exposure estimation of benzo[a]pyrene and cancer risk assessment".Journal of Toxicology and Environmental Health Part A.70 (15–16):1391–4.doi:10.1080/15287390701434182.PMID17654259.S2CID21302834.
^Aygün, SF; Kabadayi, F (December 2005). "Determination of benzo[a]pyrene in charcoal grilled meat samples by HPLC with fluorescence detection".Int J Food Sci Nutr.56 (8):581–5.doi:10.1080/09637480500465436.PMID16638662.S2CID35095622.
^U.S. Environmental Protection Agency (EPA), Washington, D.C. (2002). "Iron and Steel Manufacturing Point Source Category."Code of Federal Regulations,40 CFR Part 420.
^EPA (1984). "Nonferrous Metals Manufacturing Point Source Category."Code of Federal Regulations,40 CFR Part 421.
^Pott, Percivall (1775).Chirurgical Observations …. London, England: L. Hawes, W. Clarke, and R. Collins. pp. 63–68. From p. 67: "The disease, in these people [i.e., chimney sweeps], seems to derive its origin from a lodgment of soot in the rugae of the scrotum, … "
^Le Marchand, L; Hankin, JH; Pierce, LM; et al. (September 2002). "Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii".Mutat. Res.506–507:205–14.doi:10.1016/s0027-5107(02)00167-7.PMID12351160.
^Volk, David E.; Thiviyanathan, Varatharasa; Rice, Jeffrey S.; et al. (2003-02-18). "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.PMID12578353.
^Shou, M; Gonzalez, FJ;Gelboin, HV (December 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):15807–13.doi:10.1021/bi962042z.PMID8961944.
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