Phenanthrene, carcinogenic activity

The purpose of this eornpuLer project is Lo examine several polynuclear aromatic hydrocarbons and to relate their electron density patterns to their carcinogenic activity. If nucleophilic binding to DN.A is a significant step in blocking the normal transcription process of DN.A, electron density in the hydrocarbon should be positively correlated to its carcinogenic potency. To begin with, we shall rely on clinical evidence that benzene, naphthalene, and phenanthrene... 

The K-region of a polycyclic aromatic hydrocarbon is typified by the 9,10-bond of phenanthrene. According to the Schmidt-Pullman electronic theory, an unsubstituted K-region is a requirement for carcinogenic activity see A. Pullman and B. Pullman, La Cancerisation par les Substances Chimiques et la Structure Moleculaire, Masson, Paris, 1955. 

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

Phenanthrene may cause skin allergy, and is considered phototoxic. It has induced sister chromatid exchanges in Chinese hamster cells. The available data are inadequate to permit an evaluation of the carcinogenicity of phenanthrene to experimental animals however, a number of other PAHs have caused tumors in laboratory animals via oral, inhalation, and dermal exposures. A single oral dose of phenanthrene did not induce mammary tumors in rats, and a single subcutaneous injection did not result in treatment-related increases in tumor incidence in mice. Neonate mice administered intraperitoneal or subcutaneous injections of phenanthrene also did not develop tumors. No skin tumors were reported in two skin painting assays with mice. Phenanthrene was also tested in several mouse skin initiation-promotion assays. It was active as an initiator in one study, inactive as an initiator in four others, and inactive as a promoter in one study. 

PAHs are ubiquitous environmental pollutants known to be mutagenic and carcinogenic in mammalian cells [131, 132]. PAHs require metabolic activation that results in diol epoxide formation via reactions that are catalyzed by epoxide hydrolase and the CYP450 family of enzymes [133], Diol epoxides are highly reactive, particularly toward purines in DNA, forming guanine and adenine adducts that exist as as and trans stereoisomers [134]. Transcription past adducts derived from diol epoxides of benzo[o]pyrene (benzo[a]pyrene diol expoxide (B[a]PDE)), benzo[c]phenanthrene (benzo[c]phenanthrene diol epoxide (B[c]PhDE)), and dibenzo[a,l]pyrene (dibenzo[o,l]pyrene diol epoxide (B[a,l]PDE)) has been studied. 

Of the six purely-aromatic tetracyclic hydrocarbons, only chrysene, benz[a] anthracene and benzo[ft]phenanthrene possess even marginal activity but, as shown (Tables 4.1,4.2, and 4.3), many benz[a] anthracene derivatives are active, as are some benzo[c]phenanthrene derivatives. Substitution of one, two, or three methyl groups at 6, 7, 8, or 12 in benz[a] anthracene markedly increases activity [41]. Studies of N-mustard derivatives of anthracenes and benz[a] anthracenes [42] emphasise the parallelism between carcinogenic and carcino-static properties of poly-nuclear derivatives [43]. The marked influence of a small change in chemical structure is illustrated by the sequence of anti-tumour activities lO-ethyl-9-anthryl > 9-anthryl lO-methyl-9-anthryl for the change of meso substituent from Et to H to Me [42]. 

This structure-activity relationship has been supported by several findings. According to Iball index which is proportional to the fraction of subject animal that shows a carcinogenic response divided by the mean latent period, dibezo(a,l)pyrene has the maximum value of 74, benzo(a)pyrene has 72, other compounds with a bay region in their structures have values above 50 while compounds such as fluoranthene, tiiphenylene, and phenanthrene without any bay or fjord region have a value of 0 [11]. 

The pyrolytic oils from municipal solid waste contain substantial concentration of PAH consisting mainly of naphthalene, fluorene and phenanthrene and their alkylated substituents. Some species were of known carcinogenic or mutagenic activity, e.g., methylfluorenes, phenanthrenes, chrysene, and methylchrysene. The PAH were formed via Diels Alder and deoxygenation secondary reactions. Increase in reactor temperature and residence time increased PAH concentration [382]. 

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