Procarcinogen—

FIGURE 2.6 The procarcinogen benzo[a]pyrene oriented in the CYPlAl active site (stereo view) via n- n stacking between aromatic rings on the substrate and those of the complementary amino acid side chains, such that 7,8-epoxidation can occur. The substrate is shown with pale lines in the upper structures. The position of metabolism is indicated by an arrow in the lower structure (after Lewis 1996). 

A number of the polycyclic representatives have been shown to be human procarcinogens that require metabolic activation. 

In BA metabolism, the procarcinogenic BA trans-3.4-dihydrodiol (26) constitutes 1.5-4% of all the metabolites formed by rat liver microsomes (27) and a major component of the free dihydrodiols formed by mouse skin maintained in short-term organ culture (28). In this system (28). the noncarcinogenic dihydrodiols may be preferentially removed by conjugation reactions to yield water soluble products. 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

Nitrogen species, such as nitrate and nitrite, are known to be confirmed procarcinogens. The excessive input of these nitrogen compounds with food and drinking water in the presence of tertiary amines, for instance, from medicines, can lead to the formation of carcinogenic N-nitrosoamines. 

CYP1. The CYP1A subfamily contains two members, CYP1A1 and CYP1A2, which are involved in drug metabolism and have sparked considerable interest because they also seem to be associated with the metabolic activation of procarcinogens to mutagenic species. 

CYP1A2. CYP1A2 has been implicated in the activation of procarcinogenic species such as aflatoxin Bl, 2-acetylaminofluorene, and other arylamines. It tends to favor aromatic substrates, both heterocyclic aromatic substrates like caffeine and aromatic substrates like phenacetin (10). In the case of caffeine, 1A2 is the major isoform catalyzing the... 

Choice of Tissue. The next choice is that of source tissue. Preparations derived from liver are the most useful, as this tissue is a rich source of mixed-function oxygenases capable of converting procarcinogens to genetically active electrophiles. However,... 

Cell-free systems, when supplemented with relevant cofactors, are remarkably proficient, despite their crudity in generating reactive electrophiles from most procarcinogens. However, they provide at best a broad approximation of in vivo metabolism and can fail to produce sufficient quantity of a particular reactive metabolite to be detectable by the indicator cells or they can produce inappropriate metabolites that do not play a role in vivo (see Gatehouse and Tweats, 1987, for discussion). 

Figure 4. Proposed scheme for Cytochrome P-450 mediated metabolism (inactivation and activation) of procarcinogens (e.g. PAHs).

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