Polycyclic Aromatic Hydrocarbons

Early observations linked polycyclic aromatic hydrocarbons with occupational and experimental cancer. Now, di benzo(a, J)pyrene should be further investigated as one possible causative agent in lung cancer. This aromatic hydrocarbon has been found in cigarette smoke and exhaust gases from automobiles. In skin painting experiments using female Swiss mice, dibenzopyrene was found to be powerfully carcinogenic. The first attempt to relate physical properties of these agents with biological activity involved fluorescence spectra. Many studies since have been made in an attempt to correlate the exact structure of active hydrocarbons with their carcinogenic activity. Unaltered compounds like diben-zanthracene (XVI), having no functional groups per se, cannot be included in a chelation theory. Certain portions of each of the carcinogenic hydrocarbon molecules, however, show unusual reactivity to chemical agents, do bind to tissue, and are enzymatically hydroxylated. From calculations involving electron distributions in aromatic hydrocarbons by the use of molecular orbital theory, an arbitrary numerical value was assigned to each carbon carbon and carbon hydrogen bond in these molecules. Arbitrarily, each area of the carcinogenic aromatic hydrocarbon has been designated by a K, L, or M region (XVII), with assignment of a numerical value for each section. From the magnitude of the value from these regions, it is now possible to "predict" if any given compound is to be strongly, weakly or non carcinogenic. To be carcinogenic, a compound must have a K region whose value exceeds 1.290 arbitrary units, and this K region must be unsubstituted, for this is also where cellular attachments are made. To enhance carcinogenicity of the molecule, the L region must be of low reactivity toward addition reactions of the Diels Alder type. Metabolic hydroxylation takes place at the M region.

The actual mechanism of carcinogenesis is still unknown but modes of action have been proposed. The hydrocarbons do alter the mouse skin and combine with proteins (43, 44). Studies on this as well as the work on metabolism of carcinogenic hydrocarbons lead to the argument that hydroxylation is one of the main metabolic pathways. The sequence of events may be that the hydrocarbon first attaches itself to the cells via the K region (XVIII). The molecule once attached forms a dihydrodihydroxy derivative in the M region (XIX). The dihydroxy intermediate formed is, of course, a chelating agent; it may then detach itself from the cell, lose water, and become a monohydroxy phenol (XX). The K region of the molecule which was attached to the protein (XVIII) could be oxidized to the dicarboxylic acid (XXI).

There are certain phenomena that the chelation picture does not explain. These include the fact that some hydrocarbons already possessing the dihydroxy or diketo substitutions at the K region are not carcinogenic, but these substitutions could act to prevent cellular attachment. Another problem is that anthracene, also metabolized into a dihydroxy derivative, is not carcinogenic. However, the phenanthrene nucleus must be an integral part of the molecule; otherwise nucleic acid binding will not be geometrically possible. See Page 90. From hydrocarbon protein binding studies, the conclusion may be reached that enzyme proteins are altered or deleted from the cell. Perhaps the loss of trace elements can lead to the same result. No explanation can be given by the chelation hypothesis of the fact that partially hydrogenated hydrocarbons inhibit activity of some carcinogens.

The behavior of sulphur and nitrogen analogs of polynuclear hydrocarbons has, also, been reviewed, and these, too, may involve chelation. No studies could be found in the literature on the effects of trace elements on the carcinogenic process of the hydrocarbons. It would be interesting to see if other trace metals besides copper and iron are altered as a normal tissue is transformed into a neoplasm. Also, the effects of various added metals on the carcinogenic process should be investigated. Injected zinc sulfate did change the rate of growth of an induced sarcoma, but the nature of the carcinogen was not given in the abstracts.

Cholesterol, A Non Chelating Agent

A discussion of sterols as carcinogens rightfully belongs with the carcinogenic aromatic hydrocarbons, for there seems to be a possibility for the transformation of some sterols into aromatic carcinogens. In a consideration of cholesterol as a carcinogen, no chelation mechanism can be postulated. A proposal has been made that the true carcinogen is one of the transformation products and may be Δ5-choles-tene-3-one (XXII). The hydroperoxide of Δ5cholestene-3-one (XXIII) has recently been isolated and is more active. Cholesterol may be a precursor of cholanthrene. None of these chelates metals.

In this connection, the hormonal aspect of cancer initiation and control (287, 416) as well as the effect of gland removal on chemical carcinogenesis (214, 398), are quite significant, but are difficult to include in the chelate hypothesis.