Anthanthrene

File:Anthanthrene K region.png

PAHs often have bay and fjord regions, but anthanthrene does not have either one. Additionally, K and L regions exist in PAHs. These different regions all play a big role in the reactivity of PAHs. Anthanthrene only contains a reactive K region at carbon 4 and 5.{{Citation |last1=Pullman |first1=A. |title=Electronic Structure and Carcinogenic Activity of Aromatic Molecules New Developments |date=1955-01-01 |volume=3 |pages=117–169 |editor-last=Greenstein |editor-first=Jeese P. |url=https://linkinghub.elsevier.com/retrieve/pii/S0065230X08609197 |access-date=2025-03-16 |publisher=Academic Press |doi=10.1016/s0065-230x(08)60919-7 |last2=Pullman |first2=B. |series=Advances in Cancer Research |pmid=13248740 |isbn=978-0-12-006603-2 |editor2-last=Haddow |editor2-first=Alexander|url-access=subscription }} A K region is a region where the carbon-carbon bond has an ordinary double-bond character and can thus take part in addition reactions.{{Cite book |last=Cammack |first=R. |title=Oxford Dictionary of Biochemistry and Molecular Biology. |date=2006 |publisher=Oxford University Press |isbn=9780198529170 |edition=2nd |pages=371 |language=English |trans-title=K region}} Besides structural conditions, reactivity is also dependent on chemical conditions. For chemical conversion to its (toxic) metabolites, the K region needs to be in contact with a P450 enzyme. L regions can interfere with this chemical conversion that the K region undergoes, by initiating other types of reactions instead. So, for metabolites to form, the K region should be sufficiently active, and it should not be hindered by an active L region. Since anthanthrene does not have this L region, the K region can theoretically react unimpeded, forming among others carcinogenic epoxides.{{Cite journal |last1=Platt |first1=Karl L. |last2=Degenhardt |first2=Christian |last3=Grupe |first3=Stefanie |last4=Frank |first4=Heinz |last5=Seidel |first5=Albrecht |date=2002-03-01 |title=Microsomal Activation of Dibenzo[def,mno]chrysene (Anthanthrene), a Hexacyclic Aromatic Hydrocarbon without a Bay-Region, to Mutagenic Metabolites |url=https://pubs.acs.org/doi/10.1021/tx010131t |journal=Chemical Research in Toxicology |volume=15 |issue=3 |pages=332–342 |doi=10.1021/tx010131t |pmid=11896680 |issn=0893-228X|url-access=subscription }} Even though there is limited evidence of anthanthrene causing cancer in humans, it has been shown to cause skin cancer on mice after repeated exposure.{{Cite journal |last1=Cavalieri |first1=E. |last2=Mailander |first2=P. |last3=Pelfrene |first3=A. |date=1977-01-01 |title=Carcinogenic activity of anthanthrene on mouse skin |url=https://link.springer.com/article/10.1007/BF00308512 |journal=Zeitschrift für Krebsforschung und Klinische Onkologie |language=en |volume=89 |issue=2 |pages=113–118 |doi=10.1007/BF00308512 |pmid=143140 |issn=1432-1335|url-access=subscription }} Two other studies found anthanthrene to be mutagenic to human cells and cause DNA damage.{{Cite journal |last1=Desler |first1=Claus |last2=Johannessen |first2=Christian |last3=Rasmussen |first3=Lene Juel |date=2009-02-12 |title=Repair of DNA damage induced by anthanthrene, a polycyclic aromatic hydrocarbon (PAH) without bay or fjord regions |url=https://linkinghub.elsevier.com/retrieve/pii/S0009279708006169 |journal=Chemico-Biological Interactions |volume=177 |issue=3 |pages=212–217 |doi=10.1016/j.cbi.2008.10.056 |pmid=19046955 |bibcode=2009CBI...177..212D |issn=0009-2797|url-access=subscription }} Anthanthrene does however cause some debate about whether it really is carcinogenic.{{Cite journal |last1=da Silva Junior |first1=Francisco Carlos |last2=Felipe |first2=Maria Beatriz Mesquita Cansanção |last3=Castro |first3=Denis Elvis Farias de |last4=Araújo |first4=Sinara Carla da Silva |last5=Sisenando |first5=Herbert Costa Nóbrega |last6=Batistuzzo de Medeiros |first6=Silvia Regina |date=2021-06-01 |title=A look beyond the priority: A systematic review of the genotoxic, mutagenic, and carcinogenic endpoints of non-priority PAHs |url=https://linkinghub.elsevier.com/retrieve/pii/S0269749121004188 |journal=Environmental Pollution |volume=278 |pages=116838 |doi=10.1016/j.envpol.2021.116838 |pmid=33714059 |bibcode=2021EPoll.27816838D |issn=0269-7491|url-access=subscription }} One study found that the compound is inactive, even though it meets the criteria that the researchers set for carcinogenicity in PAHs, the research hypothesizes that the inactivity is caused by two very reactive carbons 11 and 12 that interfere with the epoxide formation in the K region, but suggest more research is done. Currently, there is no known antidote for anthanthrene exposure. Usually, PAH exposure is handled by symptomatic treatment.{{Cite book |last=Mumtaz, G. |first=Moiz, J. |title=Toxicological profile for polycyclic aromatic hrydocarbons |publisher=Public Health Service, & Agency for Toxic Substances and Disease Registry. |year=1995 |language=English}}

When individuals are exposed to anthanthrene, they are often not exposed to isolated anthanthrene, but rather to a complex mixture of several PAHs that include anthanthrene. Anthanthrene and other PAHs get released into the atmosphere by the incomplete combustion of organic materials. Common human sources of anthanthrene are industrial emissions, vehicle exhaust and cigarette smoke, but PAHs such as anthanthrene can also be released in the atmosphere through non-human sources such as forest fires and volcanic eruptions.

The main exposure route of PAHs is through inhalation of vapors containing PAHs, or inhalation of PAHs that are attached to dust and other particles in the air. Grilled food is also a common source of PAHs entering the body. Additionally, water sources can get contaminated by nearby sources of PAH emission. Water contamination could result in PAHs entering the body orally, however, receiving a high dose of water from the filtration plants is rare, because a high portion of PAHs are filtered out of the water.{{Cite web |date=2022-05-09 |title=All About PAHs |url=https://superfund.oregonstate.edu/resources/all-about-pahs |access-date=2025-03-17 |website=The Superfund Research Center |language=en}} So, anthanthrene exposure mostly occurs through inhalation of polluted air, or cigarette smoke, and ingestion of food.

Some professions are exposed to higher levels of PAHs, including anthanthrene. Professions with the highest exposure ( >10 μg/m³ ) are aluminium works, manufacturing of carbon electrodes, handling of molten tar or pitch, chimney sweeping and timber impregnation.{{Cite journal |last=Brits, M. |first=Schillack, V.R. |date=2006 |title=The occupational exposure of polycyclic aromatic hydrocarbons (PAHs) |url=https://www.occhealth.co.za/_assets/articles/165/649.pdf |journal=Occupational Health Southern Africa |volume=12 |issue=4 |pages=23–25}}

Currently, there are no established specific exposure limits for anthanthrene. However, regulatory agencies often set limits for PAHs as a group.{{Cite web |title=Clean and safe use due to the absence of banned carcinogenic substances - meeting strict EU safety standards |url=https://www.upmbiochemicals.com/renewable-functional-fillers/rff-technical-features/meeting-strict-eu-safety-standards/ |website=UPM Biochemicals}}

Because PAHs, such as anthanthrene, have very apolar structures, they can be tightly absorbed to organic compounds in soils and sediments, making them less accessible for biodegradation by microorganisms. However, PAHs can disappear from the soil by flushing into groundwater, irreversible sorption to soil organic matter, volatilisation, photooxidation, abiotic losses, and uptake by plants or microbial degradation.{{Cite journal |last1=Kariyawasam |first1=Thiloka |last2=Doran |first2=Gregory S. |last3=Howitt |first3=Julia A. |last4=Prenzler |first4=Paul D. |date=2022-03-01 |title=Polycyclic aromatic hydrocarbon contamination in soils and sediments: Sustainable approaches for extraction and remediation |url=https://linkinghub.elsevier.com/retrieve/pii/S0045653521034536 |journal=Chemosphere |volume=291 |issue=Pt 3 |pages=132981 |doi=10.1016/j.chemosphere.2021.132981 |pmid=34826448 |bibcode=2022Chmsp.29132981K |issn=0045-6535|url-access=subscription }}

The uptake of PAHs by plants is dependent on the type of plant, environmental conditions and the solubility of the PAH. Smaller PAHs will be less hydrophobic and more soluble in water, making it easier for root uptake and translocation.{{Cite journal |last1=Zhang |first1=Shichao |last2=Yao |first2=Hong |last3=Lu |first3=Yintao |last4=Yu |first4=Xiaohua |last5=Wang |first5=Jing |last6=Sun |first6=Shaobin |last7=Liu |first7=Mingli |last8=Li |first8=Desheng |last9=Li |first9=Yi-Fan |last10=Zhang |first10=Dayi |date=2017-09-22 |title=Uptake and translocation of polycyclic aromatic hydrocarbons (PAHs) and heavy metals by maize from soil irrigated with wastewater |journal=Scientific Reports |language=en |volume=7 |issue=1 |pages=12165 |doi=10.1038/s41598-017-12437-w |issn=2045-2322 |pmc=5610240 |pmid=28939846|bibcode=2017NatSR...712165Z }}

Next to soil-root uptake, PAHs can also enter plants in a gaseous state via foliar uptake. A plant with a high lipid content, has a higher tendency to bind PAHs. PAHs can absorb on the leaf wax's lipophilic surface and can enter internal components of the leaf, so especially plants that have a large leaf surface area have a higher potential for absorption and accumulation of PAHs. PAHs have a negative effect on the plant, where it inhibits growth and development.{{Cite journal |last1=Tarigholizadeh |first1=Sarieh |last2=Sushkova |first2=Svetlana |last3=Rajput |first3=Vishnu D. |last4=Ranjan |first4=Anuj |last5=Arora |first5=Jayati |last6=Dudnikova |first6=Tamara |last7=Barbashev |first7=Andrey |last8=Mandzhieva |first8=Saglara |last9=Minkina |first9=Tatiana |last10=Wong |first10=Ming Hung |date=2024-01-10 |title=Transfer and Degradation of PAHs in the Soil–Plant System: A Review |url=https://pubs.acs.org/doi/10.1021/acs.jafc.3c05589 |journal=Journal of Agricultural and Food Chemistry |volume=72 |issue=1 |pages=46–64 |doi=10.1021/acs.jafc.3c05589 |pmid=38108272 |bibcode=2024JAFC...72...46T |issn=0021-8561|url-access=subscription }}

Aquatic organisms are more sensitive to contamination by PAHs because of direct exposure to contaminated water, sediments, and plants. PAHs will mostly reside in their skin tissues, restricting the organism's metabolism causing biotransformation to occur through food chains.

PAH's property to persist in soils and sediments, leads to a constant contamination of aquatic organisms and plants with PAHs. PAHs can accumulate in organisms through different trophic levels, leading to bioaccumulation and biomagnification. This poses a threat to life, considering PAH's carcinogenic properties.

Three different pathways have been identified for the biotransformation of anthanthrene in bacteria: pathway I, II, and III. These pathways lead to different types of metabolites. These metabolites are often just excreted but can also be toxic.

In pathway I, K-region metabolites are produced through an epoxide formation between the carbons in this region. This pathway is enzymatically catalyzed by the P450 2B subfamily, that is responsible for monooxygenation. The metabolites 4,5-dihydrodiol, 9-phenol-4,5-dihydrodiol and phenol-dihydrodiol are formed by the enzyme epoxide hydrolase. This enzyme detoxifies the genotoxic 4,5-epoxide formed at the K region.

In pathway II, polynuclear quinones are formed. This pathway is not catalyzed enzymatically like pathway I, but through autoxidation. This means that the conversion to 1,6-quinone, 3,6-quinone (genotoxic) and 6,12-quinone happens by oxidation through one electron.

Metabolites formed in pathway III are mono- and diphenols. The pathway is, like pathway I, enzymatically catalyzed, but rather than the P450 2B subfamily, the P450 1A subfamily plays a major role. The P450 1A subfamily causes monooxygenation at the ring in anthanthrene with carbons 1, 2 and 3 (the ring on the top right), after which by further oxidation the mono- and diphenols are formed.

Molecules like benzo[a]pyrene and chrysene, chemically similar to anthanthrene, have binding affinity to the blood protein albumin, allowing transport through the body.{{Cite web |title=T3DB: Anthanthrene |url=https://www.t3db.ca/toxins/T3D0632 |access-date=2025-03-17 |website=www.t3db.ca}} This hints that anthanthrene could also be transported through the body mediated by albumin (note: there is no experimental proof for this). It is suspected that anthanthrene is primarily metabolized in the liver.{{Citation |last=Humans |first=IARC Working Group on the Evaluation of Carcinogenic Risks to |title=Summary of Data Reported and Evaluation |date=2010 |work=Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures |url=https://www.ncbi.nlm.nih.gov/books/NBK321713/ |access-date=2025-03-17 |publisher=International Agency for Research on Cancer |language=en}}

Research suggests that anthanthrene 4,5-epoxide and the 3-hydroxyanthanthrene are the metabolites of anthanthrene that are most mutagenic.

The epoxide ring at the 4,5-position is highly strained and electrophilic, making it susceptible to nucleophilic attack by DNA bases, particularly the N7 position of guanine, which results in DNA adducts. If not repaired, these adducts can lead to replication errors, base substitutions (e.g., G→T transversions), and strand breaks, contributing to carcinogenesis.{{Cite journal |last1=Hwa Yun |first1=Byeong |last2=Guo |first2=Jingshu |last3=Bellamri |first3=Medjda |last4=Turesky |first4=Robert J. |date=2020 |title=DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans |journal=Mass Spectrometry Reviews |language=en |volume=39 |issue=1–2 |pages=55–82 |doi=10.1002/mas.21570 |issn=1098-2787 |pmc=6289887 |pmid=29889312|bibcode=2020MSRv...39...55H }}

3-hydroxyanthanthrene is further biotransformed into multiplequinones, primarily 3,6-quinone. These quinones are electrophilic making it possible to react with nucleophiles like DNA bases. The primary site of attack is the guanine (N7 position), but adenine (N3) and cytosine (N3) can also be involved. The attack on the DNA base causes DNA adducts which lead to replication errors, base substitutions (e.g., G→T transversions), and strand breaks, contributing to carcinogenesis.{{Cite journal |last1=Xiong |first1=Yue |last2=Kaw |first2=Han Yeong |last3=Zhu |first3=Lizhong |last4=and Wang |first4=Wei |date=11 November 2021 |title=Genotoxicity of quinone: An insight on DNA adducts and its LC-MS-based detection |url=https://www.tandfonline.com/doi/full/10.1080/10643389.2021.2001276 |journal=Critical Reviews in Environmental Science and Technology |volume=52 |issue=23 |pages=4217–4240 |doi=10.1080/10643389.2021.2001276 |issn=1064-3389|url-access=subscription }}

It is important to note that much of our understanding of anthanthrene's molecular mechanism of action is inferred from studies on similar PAHs. Direct experimental evidence specific to anthanthrene is limited, and further research is needed to confirm its toxic effects.

Through biotransformation, anthanthrene is converted into various metabolites. Primary among these are 3-hydroxyanthanthrene and anthanthrene 3,6-quinone, in rats.{{Cite journal |last1=Degenhardt |first1=Christian |last2=Bors |first2=Wolf |last3=Stettmaier |first3=Kurt |last4=Seidel |first4=Albrecht |last5=Frank |first5=Heinz |last6=and Platt |first6=Karl-L. |date=22 September 2006 |title=Metabolic Activation of Anthanthrene: Significance of Stable Radicals Derived from its Key Metabolite 3-Hydroxyanthanthrene |url=https://www.tandfonline.com/doi/abs/10.1080/10406639608034683 |journal=Polycyclic Aromatic Compounds |volume=10 |issue=1–4 |pages=85–92 |doi=10.1080/10406639608034683 |issn=1040-6638|url-access=subscription }} Further metabolic processing yields additional metabolites that have been described before, with significantly increased water solubility compared to the original compound. This allows for excretion through 3 routes: bile, feces, and urine.{{Cite book |last=Larsen |first=J.C. |title=Polyaromatic Hydrocarbons (PAH). Evaluation of health hazards and estimation of a quality criterion in soil |publisher=The Danish Environment Protection Agency |year=2013 |isbn=978-87-93026-78-0 |location=Copenhagen, Denmark |pages=3–23 |language=English}}

PAHs, in general, are mostly excreted through bile, and less in feces and urine. For example, studies on benzo[a]pyrene showed that bile "accounts for [excretion of] approximately 60% of an intravenous dose, while urinary excretion represented only about 3%". This pattern is in general true for higher molecular weight PAHs, like anthanthrene and benzo[a]pyrene. Unfortunately, studies specifically focusing on anthanthrene excretion are limited.

Studies on other PAHs have shown altering urinary excretion percentages, with phenanthrene, pyrene, and benzo[a]pyrene having urinary excretion efficiencies of 40.4%, 11.4%, and 6.3%, respectively. Anthanthrene's urinary excretion rate likely falls on the low side, like benzo[a]pyrene, because of its high molecular weight.{{Cite journal |last1=Motorykin |first1=Oleksii |last2=Santiago-Delgado |first2=Lisandra |last3=Rohlman |first3=Diana |last4=Schrlau |first4=Jill E. |last5=Harper |first5=Barbara |last6=Harris |first6=Stuart |last7=Harding |first7=Anna |last8=Kile |first8=Molly L. |last9=Massey Simonich |first9=Staci L. |date=2015-05-01 |title=Metabolism and excretion rates of parent and hydroxy-PAHs in urine collected after consumption of traditionally smoked salmon for Native American volunteers |journal=Science of the Total Environment |volume=514 |pages=170–177 |doi=10.1016/j.scitotenv.2015.01.083 |issn=0048-9697 |pmc=4361301 |pmid=25659315|bibcode=2015ScTEn.514..170M }}

Glucuronic acid conjugates of PAH metabolites in the gastrointestinal tract can be broken down by microorganisms. These metabolites are then released and can be reabsorbed in a process called enterohepatic circulation. This could be happening for anthanthrene metabolites as well, allowing for longer exposure times in the body. Half-life data are unavailable for anthanthrene, but other studies on PAHs show relatively rapid excretion. Research on urinary PAH metabolites has shown that 58-79% of urinary OH-PAHs are often excreted within the first 12 hours after exposure.{{Cite journal |last1=Li |first1=Zheng |last2=Romanoff |first2=Lovisa |last3=Bartell |first3=Scott |last4=Pittman |first4=Erin N. |last5=Trinidad |first5=Debra A. |last6=McClean |first6=Michael |last7=Webster |first7=Thomas F. |last8=Sjödin |first8=Andreas |date=2012-07-16 |title=Excretion Profiles and Half-Lives of Ten Urinary Polycyclic Aromatic Hydrocarbon Metabolites after Dietary Exposure |journal=Chemical Research in Toxicology |volume=25 |issue=7 |pages=1452–1461 |doi=10.1021/tx300108e |issn=0893-228X |pmc=4618384 |pmid=22663094}} It is expected that smaller PAHs will be excreted faster than larger PAHs, such as anthanthrene.

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{{PAHs}}

Category:Polycyclic aromatic hydrocarbons

Category:Hexacyclic compounds