Polycyclic Aromatic Hydrocarbons - Organic Pollutants: An Ecotoxicological Perspective - page 187

activation as well as detoxication. The types of P450 involved determine the position
of metabolic attack (see Section 9.3). Cytochrome P450 1A1, for example, activates
benzo[ a ]pyrene by oxidizing the bay region to form a mutagenic diol epoxide. The
tendency for PAHs to be activated as opposed to detoxified depends on the balance
of P450 forms, and this balance is dependent on the state of induction. Many PAHs,
PCDDs, PCDFs, coplanar PCBs, and other planar organic pollutants are inducers
of P450s belonging to Family 1A. Thus, activation of PAH may be enhanced owing
to the presence of pollutants that induce P450 1A1/1A2, forms that are particularly
implicated in the process of activation (Walker and Johnston 1989).

9.5 toxIcIty

PAHs are rather nonreactive in themselves, and appear to express little toxicity.
Toxicity is the consequence of their transformation into more reactive products, by
chemical or biochemical processes. In particular, the incorporation of oxygen into
the PAH ring structure has a polarizing effect; the electron-withdrawing properties
of oxygen leading to the production of reactive species such as carbonium ions. This
is evidently the reason why PAHs become more toxic to fish and Daphnia following
exposure to ultraviolet (UV) radiation (Oris and Giesy 1986, 1987); photooxidation
of PAH to reactive products increases toxicity.
Much research on the toxicity of PAH has been concerned with human health
hazards, and has focused on their mutagenic and carcinogenic action. These two
properties are to some extent related, because there is growing evidence that cer-
tain DNA adducts formed by metabolites of carcinogenic PAHs become fixed as
mutations of oncogenes or tumor-suppressor genes that are found in chemically pro-
duced cancers (Purchase 1994). Typical mutations occur at specific codons in the ras,
neu, or myc oncogenes or in P53, retinoblastoma or APC tumor suppressor genes.
These genes code for proteins involved in growth regulation, with the consequence
that mutated cells have altered growth control. One example of such a carcinogenic
metabolite is the 7,8-diol-9,10 oxide of benzo[ a ]pyrene (Figure 9.2). More generally,
many compounds found to be mutagenic in bacterial mutation assays (e.g., the Ames
test) are also carcinogenic in long-term dosing tests with rodents. However, a sub-
stantial number of carcinogens act by nongenotoxic mechanisms (Purchase 1994).
Benzo[ a ]pyrene is converted to its 7,8-diol-9,10 oxide by the action of cytochrome
P450 1A1 and epoxide hydrolase, as shown in Figure 9.2. In one of its enantiomeric
forms, this metabolite can then form DNA adducts by alkylating certain guanine
residues (Figure 9.3). The metabolite acts as an electrophile, due to strong carbo-
nium ion formation on the 10 position of the epoxide ring, which is located in the
bay region. The epoxide ring cleaves, and a bond is formed between C10 of the PAH
ring and the free amino group of guanine. The oxygen atom of the cleaved epoxide
ring acquires a proton, thus leaving a hydroxyl group attached to C9. This adduct,
similar to the others formed between reactive metabolites of PAHs and DNA, is
bulky and can be detected by P32 postlabeling and immunochemical techniques
(e.g., Western blotting). It has been proposed that there is a particular tendency for
strong carbonium ion formation to occur on the bay region of PAHs, and that such