Carcinogenic polycyclic aromatic activation

Schmahl, D., R. P. Deutsch-Wenzel, H. Brune, P. Schneider, U. Mohr, M. Habs, F. Pott, and D. Steinhoff, Biological Activity, in Environmental Carcinogens Polycyclic Aromatic Hydrocarbons (G. Grimmer, Ed.), pp. 157-220, CRC Press, Boca Raton, FL, 1983. 

One of the most potent carcinogenic polycyclic aromatic hydrocarbons. In animals, large single and multiple doses produce tumors of the skin, breast, and stomach or leukemias, regardless of route of administration. It is a strong mutagen after metabolic activation.2-4... 

Shimada, T. (2006) Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab. Pharmacokinet. 21, 257-276. 

Particles also have direct health effects when inhaled. This is especially true of very small particles that can be carried into the innermost parts (alveoli) of lungs. The particles that are most damaging are very small ones less than 2.5 pm in size (less than 1/30 the diameter of a human hair) designated PM2 5 These are mostly condensation aerosols and may contain toxic elements, such as arsenic, acids, such as H2SO4, and carcinogenic polycyclic aromatic hydrocarbons including benzo(a)-pyrene. Because of their very small size, these particles have very high surface-to-volume ratios and biochemically active surfaces. 

Feeder-layer experiments depend on the ability of a chemical activated by an irradiated feeder layer of metabolizing cells to induce SCEs in exponentially dividing tester cells. Syrian hamster secondary embryo cultures that have been shown to metabolize various carcinogenic polycyclic aromatic hydrocarbonsare used as the feeder layer, and Chinese hamster V79 cells are the tester cells. The irradiated embryo culture cells are mixed with the V79 cells before being plated in petri dishes. Chemicals are added 24 hr later with BrdUrd, and the cells are fixed after an additional 24 hr. Positive results are obtained with benzo[a]pyrene, 3-methylcholanthrene, and dimethylben-zanthracene, none of which induces SCEs in the absence of the feeder layer. 

Benzo[a]pyrene, a molecule with five, fused, hexagonal rings, is among the most carcinogenic of the polycyclic aromatic hydrocarbons (PAHs). Such biological activity may be related to the electronic structure of benzo[a]pyrene and its metabolites. Ionization energies of these molecules therefore have been investigated with photoelectron spectroscopy [28]. 

Man has served as the unintentional guinea pig for the identification of some major classes of carcinogens. These include the polycyclic aromatic hydrocarbons (PAH), or polyarenes, which have been identified as the active components of soot, which was recognized by the London surgeon Percivall Pott two centuries ago as responsible for cancer of the scrotum in chimney sweeps. Subsequently, polycyclic hydrocarbons have been implicated as agents responsible for skin cancer in other occupations such as shale oil distillation and mule spinning in the cotton industry. 

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. 

Covalent binding of chemical carcinogens to cellular macromolecules, DNA, RNA and protein, is wel1-accepted to be the first step in the tumor initiation process ( 1, 2). Most carcinogens, including polycyclic aromatic hydrocarbons (PAH), require metabolic activation to produce the ultimate electrophilic species which react with cellular macromolecules. Understanding the mechanisms of activation and the enzymes which catalyze them is critical to elucidating the tumor initiation process. 

Oxidation is intimately linked to the activation of polycyclic aromatic hydrocarbons (PAH) to carcinogens (1-3). Oxidation of PAH in animals and man is enzyme-catalyzed and is a response to the introduction of foreign compounds into the cellular environment. The most intensively studied enzyme of PAH oxidation is cytochrome P-450, which is a mixed-function oxidase that receives its electrons from NADPH via a one or two component electron transport chain (10. Some forms of this enzyme play a major role in systemic metabolism of PAH (4 ). However, there are numerous examples of carcinogens that require metabolic activation, including PAH, that induce cancer in tissues with low mixed-function oxidase activity ( 5). In order to comprehensively evaluate the metabolic activation of PAH, one must consider all cellular pathways for their oxidative activation. 

---