Activation of PAHs

Epidemiologic studies in Japan indicate an increased risk of stomach cancer owing to consumption of broiled fish and meats (116). In the United States, stomach cancer incidence has steadily declined since the 1940s, whereas consumption of broiled food has increased (108). In addition, the average human intake of PAHs is only 0.002 of that required to produce cancer in half of animals fed. Test results are often contradictory (117) and many components of food, such as vitamin A, unsaturated fatty acids, thiols, nitrites, and even saUva itself, tend to inhibit the mutagenic activity of PAHs (118—120). Therefore, the significance of PAHs in the human diet remains unknown (121,109). 

At present a variety of studies with PAH, as well as other chemicals, suggest that metabolic activation in target tissues can occur by one-electron oxidation (6,7). The electrophilic intermediate radical cations generated by thTs mechanism can react directly with various cellular nucleophiles. In this paper, we will discuss chemical, biochemical and biological evidence which indicates that one-electron oxidation plays an important role in the metabolic activation of PAH. 

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. 

Methyl substitution in strategic positions in polyarenes frequently results in notable enhancement of carcinogenic activity. Thus, methyl substitution at a bay region tends to markedly increase the biological activity (14). Moreover, carcinogenic activities of PAHs are often strongly affected by fluorine substitution at proper molecular sites (3, 15). 

The reason that one-electron oxidation is suggested as playing a central role in the metabolic activation of PAHs concerns certain features of the cation-radicals that are common to the most potent carcinogens of the family. 

It was early established that at least for PAH, which as isolated contains the catalytic iron in the ferric high-spin (S = 5/2) state, the Fe111 is reduced to Fe11 by BH4. This is termed reductive activation of PAH and in vitro this reduction is an obligate step that occurs in the pre-steady-state period (20). A midpoint potential at pH 7.25 (Em (Fein/Fen)) of +207 10 mV was calculated for the iron in hPAH, which seems to be adequate for a thermodynamically feasible electron transfer from BH4 (Em (q-BH2/ BH4) = +174mV) (40). 

OAT4 is expressed in the kidney and placenta (155), and in the kidney, unlike other human isoforms, it is expressed on the brush border membrane of the proximal tubules (156). It accepts sulfate conjugates, ochratoxin A, and PAH, although the transport activity of PAH is quite low (155). As in the case of... 

The mechanism of action for diesel fuels is not well characterized due to the complexity of its petroleum hydrocarbon mixture. The presence of additives that improve fuel combustion or prevent microbial growth may contribute to toxicity. Based on research conducted with individual components of diesel fuels, the primary mechanism of action for central nervous system (CNS) depression from diesel fuel is the reversible, physical interaction of the aromatic and aliphatic hydrocarbons with cell membranes. Renal toxicity is possibly attributed to oxidative metabolites of some of the aromatic constituents. Eye and skin injury are attributable to direct irritant action and the high lipid solubility that may dissolve protective skin oils and allow penetration into the skin tissue. The dermal carcinogenesis observed in rodents subjected to chronic dermal exposure to diesel may be attributed to the genotoxic activity of PAHs and the promoting activity of repeated dermal injury. 

Metabolic activation of PAHs consists of an oxidation of the rings of unsubstituted PAHs. These oxidations are carried out by mixed function oxidases of the liver which contain cytochromes P450 and P448 and require reduced nicotine adenine dinucleotide and oxygen. In this oxidation, an epoxide intermediate is formed which has been shown to have the requisite chemical reactivity to bind covalently with DNA and histones and to serve as the ultimate carcinogenic form of PAH. Administration of 3-MC to rats increased hepatic nuclear proteins and caused a turnover of protein of the endoplasmic reticulum. Studies of " C amino acid incorporation showed that 3-MC causes increased protein synthesis and reduced degradation of protein. 

Varanasi, U., W.M. Baird and T.A. Smolarek. Metabolic activation of PAHs in subcellular fractions and cell cultures from aquatic and terrestrial species. In Metabolism of Polycyclic Aromatic Hydrocarbons in the Aquatic Environment, edited by U. Varanasi, Boca Raton, FL, CRC Press, 1989, Chapter 6. 

Individuals who undergo a rapid reduction in body fat may be at risk from increased toxicity because of the systemic release and activation of PAHs that had been stored in fat. The metabolism of benzo[a]pyrene in hepatocytes in v/fro from rats fed high-fat (as corn oil) diets was decreased (Zaleski et al. 1991). This effect was not due to a decrease in the activity of AHH. The authors postulated that the high-fat diets allowed benzo[a]pyrene, which is highly lipophilic, to become sequestered in lipid droplets and, therefore, become inaccessible to the P-450 enzymes. 

Murray RW, Kong W. 1994. Activation of PAH by ozone derived oxidants results at ambient conditions. Polycyclic Aromatic Hydrocarbons 5 139-147. 

Figure 6.3. The metabolic activation of PAH through diol epoxide, radical cation, o-quinone, and arene oxide activation mechanisms.

Scheme 6.3 Metabolic activation of PAHs to radical cations.

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