Benzo(j)fluoranthene

Structure and synthesis

BjF consists of two naphthalene-like structures which are fused by a cyclopentane structure. This cyclopentane is not included in the aromaticity of the molecule. BjF can be obtained when either 2-(1-chloroethenyl)benzo[c]phenanthrene or 6-(1-chloroethenyl)chrysene is treated by flash vacuum thermolysis (FVT) at high temperatures (above 900 °C) followed by ring rearrangements (ring contraction/expansion) to selectively yield BjF. Benzo[k]fluoranthene may also be converted via similar processes to BjF by FVT at temperatures of at least 1100 °C (6% yield) or at least 1200 °C (11% yield) with 38% mass recovery.

Reactivity

BjF can be functionalized by means of electrophilic aromatic substitution. In the body it is metabolized into phenols (3,4,6 or 10 hydroxy), dihydrodiols (4,5 and 9,10) and 4,5-dioneE.H. Weyand et al. (1993) "Detection of the Major DNA Adducts of Benzo[j]fluoranthene in Mouse Skin: Nonclassical Dihydrodiol Epoxides" Chemical Research in Toxicology 6 (fig. 1).

Mechanism of action

BjF is categorized by the IARC as possibly carcinogenic to human beings, like many other PAHs, on the basis of sufficient evidence in animals. For example, BjF is active as a tumor initiator on mouse skin and is carcinogenic in both mouse skin and in rat lungs. Recently, BjF was also found to induce tumors in newborn mouse lung and liver.J.E. Rice et al. (1 December 1987) "Identification of Tumorigenic Metabolites of Benzo[j]fluoranthene Formed in Vivo in Mouse Skin" Cancer Research 47, 6166-6170 The mechanism of actions of BjF is similar to other PAHs. The diolepoxide mechanism involves formation of stable and unstable DNA adducts, mainly at G and A, which can lead to mutations in proto-oncogenes (RAS) and tumour-suppressor genes (P53). Many polycyclic aromatic hydrocarbon diolepoxides and their precursor diols and epoxides are tumorigenic in animals. The radical cation mechanism involves generation of unstable adducts at G and A, leading to apurinic sites and mutations in HRAS. Orthoquinone formation could lead to stable and unstable DNA adducts and generation of reactive oxygen species, inducing mutations in P53.

Toxicity

PAHs

One of the earliest connection between PAHs, combustion, and cancer was established by Cook and co-workers with the isolation of the carcinogen benzo[a]pyrene from coal tar extract. Benzo[a]pyrene now has been well characterized in toxicology reports and is a known potent carcinogen.Denissenko, Mikhail F., et al. "Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53." Science 274.5286 (1996): 430-432. Benzo[a]pyrene requires metabolic activation to become, ultimately, BPDE ((±)-anti-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) which binds to the DNA to form a covalent trans adducts at the N2 position of guanine.Singer, B., and D. Grunberger. "Metabolic activation of carcinogens and mutagens." Molecular Biology of Mutagens and Carcinogens. Springer US, 1983. 97-141. Hereafter binding to DNA at cancer hotspots, especially in the P53 tumour suppressor gene at codons: 157, 248 and 273 (figure 3), it has the possibility of inducing lung cancer.Denissenko, Mikhail F., et al. "Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53." Science 274.5286 (1996): 430-432. Structural similarity of PAHs contributes to the similarity in metabolism, biotransformation and toxicology. Benzo[a]pyrene has been extensively reviewed and is used as a model for the toxicology and metabolism of other PAHs.Agency for Toxic Substances and Disease Registry (ATSDR). (1995) "Toxicological profile for Polycyclic Aromatic Hydrocarbons (PAHs)" Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Benzo[''j'']fluoranthene

Specific studies on BjF showed that it exhibits mutagenic toxicity in S. typhimurium TA98 and TA1000 under the presence of microsomal activation. BjF can form DNA-adducts, covalently binding of chemicals to DNA can result in strand breaks and DNA damage, which ultimately leads to mutations.Agency for Toxic Substances and Disease Registry (ATSDR). (1995) "Toxicological profile for Polycyclic Aromatic Hydrocarbons (PAHs)" Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. In mice studies BjF induced tumorigenic activity on the skin, lung adenomas and liver adenomas/hepatomas.LaVoie, Edmond J., et al. "Tumour initiating activity of dihydrodiols of benzo[b]fluoranthene, benzo[j]fluoranthene, and benzo[k]fluoranthene." Carcinogenesis 3.1 (1982): 49-52. Habs, M., D. Schmähl, and J. Misfeld. "Local carcinogenicity of some environmentally relevant polycyclic aromatic hydrocarbons after lifelong topical application to mouse skin." Archiv für Geschwulstforschung 50.3 (1979): 266-274. Weyand, E. H., et al. "Effect of fluorine substitution on benzo[j]fluoranthene genotoxicity." Chemico-Biological Interactions 84.1 (1992): 37-53 Lung implantation of BjF also induced lung epidermoid carcinomas in 3-month-old female rats.Deutsch-Wenzel, Reintraud P., et al. "Experimental studies in rat lungs on the carcinogenicity and dose-response relationships of eight frequently occurring environmental polycyclic aromatic hydrocarbons." Journal of the National Cancer Institute 71.3 (1983): 539-544 Tail vein injection of BjF also causes covalently binding to mouse hemoglobin and serum proteins, with binding to serum proteins being 10-fold higher than to hemoglobin.Agency for Toxic Substances and Disease Registry (ATSDR). (1995) "Toxicological profile for Polycyclic Aromatic Hydrocarbons (PAHs)" Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

References

References

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