Benzo(c)fluorene

Benzofluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzofluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen (not classifiable as to its carcinogenicity to humans). Other names for benzofluorene are 7H-benzofluorene, 3,4-benzofluorene, and NSC 89264. Benzofluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzofluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen (not classifiable as to its carcinogenicity to humans). Other names for benzofluorene are 7H-benzofluorene, 3,4-benzofluorene, and NSC 89264. The structure of benzofluorene is depicted in the infobox on the right. It is an aromatic fluorene-derived molecule with an extra benzene ring. This benzene ring is attached to carbon 3 and 4 of the fluorene-derived molecule. The 3D structure of benzofluorene is depicted in the infobox on the right as well. It is mostly flat, because it consists of 3 aromatic rings. Only the 2 hydrogen atoms on the 5 ring are oriented into the 3D plane. Benzofluorene occurs naturally in tar, but can also be manually synthesized in a four step process, which is depicted in the picture below. The starting product is 1-indanone (1). This is brominated in a substitution reaction to 3-bromoindanone (2) using the reagent N-bromosuccinimide. This substance is dehydrobrominated to 2H-inden-1-one (3) using the reagent triethylamine. Benzofluorenone-9 (4) is generated by self-condensation of 2H-inden-1-one, when heated. The final step is reduction of this compound with hydrazine hydrate, generating benzofluorene (5). In general PAH carcinogenesis involves activation by the enzyme P-450 to diol epoxide metabolites with an epoxide ring in the bay or fjord region. These diol epoxide metabolites are reactive and capable of forming DNA adducts (see the adjacent image).While benzofluorene does not have a bay or fjord region it does undergo a similar transformation with a pseudo-bay region that reacts instead. The type of cytochrome P 450 involved is thought to be CYP1A1. The biotransformation is depicted in the image below. First benzofluorene (1) is transformed into trans-3,4-dihydrodiol (2). This substance is transformed by CYP1A1 into the highly carcinogenic metabolites anti-diolepoxide (3) and syn-diolepoxide (4). Benzofluorene and PAHs in general are mostly absorbed via ingestion, inhalation, and dermal contact. Also, depending on the vehicle (transport medium) in which the PAHs are located, the percentages of absorption can differ. Ingestion of benzofluorene makes it a very potent lung tumorigenIn particular, benzofluorene is better absorbed in the lungs. Once it is absorbed, benzofluorene enters the lymph, circulates in the blood and is metabolized. The distribution of PAHs depends on their lipophilicity and probably benzofluorene can easily cross the cell membrane, because of this lipophilicity. This has been proven for similar substances like fluorene and fluoranthene, but has yet to be investigated for benzofluorene. Benzofluorene is mainly metabolized by the CYP enzymes in the liver. There is also evidence that a larger number of metabolites are formed in the lungs, which might explain why benzofluorene is such a potent lung tumorigen. It is possible that benzofluorene may have a unique (and still unknown) mechanism of activation or transportation, which explains why the lungs are targeted.The initial steps of the metabolism, the phase I biotransformation, are described above. For many PAHs it has been proven that they are conjugated, in phase II, with either glucuronide, sulfate or glutathione. More research on this topic is necessary for benzofluorene. Glucuronide and sulfate conjugates of PAH metabolites are generally excreted in the bile and urine.Glutathione conjugates are further metabolized to mercapturic acids in the kidney and are excreted in the urine. The hydroxylated metabolites of the PAHs are excreted in human urine both as free hydroxylated metabolites and as hydroxylated metabolites conjugated to glucuronic acid and sulfate.