Carcinogens Polycyclic hydrocarbons

Synthesis of the Dihydrodiol and Diol Epoxide Metabolites of Carcinogenic Polycyclic Hydrocarbons... 

Grimmer, G., Hildebrandt, A., (1975) "Investigations on the Carcinogenic Burden by Air Pollution in Man XII. Assessment of the Contribution of Passenger Cars to Air Pollution by Carcinogenic Polycyclic Hydrocarbons",... 

With carcinogenic polycyclic hydrocarbons, dihydrodiols are further metabolized to epoxides as shown in chapter 7, Figure 2. This epoxide-diol may then react with weak nucleophiles such as nucleic acids. 

An example of the second type of chiral effect in metabolism is afforded by benzofa]-pyrene, also discussed in more detail in chapter 7. This carcinogenic polycyclic hydrocarbon is metabolized stereos elec lively by a particular cytochrome P-450 isozyme, CYP1A1, to the (+)-7R,8S oxide (chap. 7, Fig. 5.2), which in turn is metabolized by epoxide hydrolase to the (—)-7R,8S dihydrodiol. This metabolite is further metabolized to (- -)-benzo[aIpyrene, 7R,8S dihydrodiol, 9S,10R epoxide in which the hydroxyl group and epoxide are trans and which is more mutagenic than other enantiomers. The (—)-7R,8S dihydrodiol of benzo[aIpyrene is 10 times more tumorigenic than the (+)-7R,8S enantiomer. It was reported that in this case the configuration was more important for tumorigenicity than the chemical reactivity. 

Huberman, E., and L. Sachs. Mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycyclic hydrocarbons. 

Newbold, R.F., C.B. Wigley, M.H. Thompson, and P. Brookes. Cell-mediated mutagenesis in cultured Chinese hamster cells by carcinogenic polycyclic hydrocarbons Nature and extent of the associated hydrocarbon-DNA reaction. Mutat. Res. 43 101-116,... 

This polycyclic, aromatic hydrocarbon is produced continuously by almost all plants, irrespective of their habitat, and remains qualitatively and quantitatively constant. The normal content of the carcinogenic 3.4 -benzpyrene equals 1 pg/lOO g dried plant material. (The assumed quantity of carcinogenic polycyclic hydrocarbons ingested daily with food and drinking water is calculated at 10 ig/day.) Food of animal origin, even in roasted, smoked or grilled form, contains substantially less benzpyrene than plants do. 

Simon, Z., Ciubotariu, D. and Balaban, A.T. (1985b). Reactivity and Stereochemical Parameters in QSAR for Carcinogenic Polycyclic Hydrocarbon Derivates. In QSAR and Strategies in the Design in Bioactive Compounds (Seydel, J.K., ed.), VCH Verlagsgesellschaft, Weinheim (Germany), pp. 370-373. 

Ames, B. N., Sims, P., Grover, P. L. Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens. Science 176, 47 (1972). 

Casto BC, Pieczynski WJ, Dipaolo JA. 1973. Enhancement of adenovirus transformation be pretreatment of hamster cells with carcinogenic polycyclic hydrocarbons. Cancer Res 33 819-824. 

Chu EW, Malmgren RA. 1965. An inhibitory effect of vitamin A on the induction of tumors in the forestomach and cervix in the Syrian hamster by carcinogenic polycyclic hydrocarbons. Cancer Res 25 884-895. 

Huberman E. 1975. Mammalian cell transformation and cell-mediated mutagenesis by carcinogenic polycyclic hydrocarbons. Mutat Res 29 285-291. 

Old LJ, Benacerraf B, Carswell E. 1963. Contact reactivity to carcinogenic polycyclic hydrocarbons. Nature 198 1215-1216. 

Slaga TJ, Jecker L, Bracken WM, et al. 1979. The effects of weak or non-carcinogenic polycyclic hydrocarbons on 7,12- dimethylbenz(a)anthracene and benzo(a)pyrene skin tumor-initiation. Cancer Lett 7 51-59. 

The coplanarity of benzo[ajpyrene and many carcinogenic polycyclic hydrocarbons is of interest. It has been suggested that this flat structure allows intercalation of the hydrocarbon within the DNA molecule, thereby facilitating reaction of the intermediate with the nucleic acid. 

Yu, H., Environmental carcinogenic polycyclic hydrocarbons photochemistry and phototoxicity,... 

Benzo(a)pyrene is present in much larger concentrations than is any other carcinogenic polycyclic hydrocarbon. The inability to account for the carcinogenicity of the tobacco products, except to a very minor degree, by the amonnt of benzo(a)pyrene present was unanticipated. Both Drnckrey (1056) and Wynder (4300) emphasized that the benzo(a)pyrene concentration of various tobacco and smoke preparations is only sufficient to account for a very small part of the carcinogenicity of these materials [see pp. 144-145 in (3999)]. 

Carcinogenic polycyclic hydrocarbons occur in water either in the dissolved form (Table 3.28) or adsorbed on various particles. The content... 

O Neill, J.P., Brimer, P.A., Machanoff, R., Hirsch, G.P., Hsie, A.W. 1977. A quantitative assay of mutation induction at the hypoxanthine-quanine phosphoribosyl transferase locus in Chinese hamster ovary cells (CHO/HGPRT System) Development and definition of the system. Mutat. Res. 45 91-101. Huberman, E. 1976. Cell-mediated mutagenicity of different genetic loci in mammalian cells by carcinogenic polycyclic hydrocarbons. In Screening Tests in Chemical Carcinogenesis, eds. R. Montesano, H. Bartsch,... 

Huberman, E., and Sachs, L., "Mutability of Different Genetic Loci In Mammalian Cells by Metabollea I Iy Activated Carcinogenic Polycyclic Hydrocarbons", Proc. Natl. Acad. Scl., USA (1976), 73 188-192. 

Aside from whether they are directly active per se, or merely as precursors of active metabolic intermediates, carcinogenic polycyclic hydrocarbons can initiate carcinomas (e.g. epithelioma) at the point of application on the skin (the commonest mode of study), or can lead to distant tumours, as in bronchogenic cancer [23]. The mechanism probably includes solubilisation of the carcinogens (by proteins, nucleoproteins, fatty acid esters, etc. or even in aqueous solution [58]), so as to enable them to traverse the dermis (possibly via an external solvent) and thus react in the epidermis, which possesses a lipoid barrier. Alternatively, appendageal transport routes (hair follicles, sweat glands, sebaceous glands) may be used [59]. When carcinogens act at a distance, as with liver, breast, bladder and other internal cancers, an internal transport mechanism or medium is evidently needed. 

J. A. DiPaolo, R. L. Nelson, and P. J. Donovan, Morphological, oncogenic, and karyological characteristics of Syrian hamster embryo cells transformed in vitro by carcinogenic polycyclic hydrocarbons, Cancer Res. 31, 1118-1127 (1971). 

Comparative studies of the frequency of mutations to AG or TG resistance induced in normal and XP cells by exposure to V-AcO-AAF or to reactive metabolites of several carcinogenic polycyclic hydrocarbons, e.g., benzo[a]-... 

Compounds which have been reported to induce microsomal enzymes include barbiturates and non-barbiturate sedatives, antihistaminics. analgesics, anti-inflammatory compounds, halogenated hydrocarbon insecticides, certain carcinogenic polycyclic hydrocarbons, and most recently, aromatic constituents of certain conifer woods. Based on differences in their profile of biologic effects, most of these agents can be placed into one of three general groups (1) the phenobarbital type, (2) the polycyclic hydrocarbon type and (3) anabolic steroids. 

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