The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis

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Abstract
The metabolism of xenobiotics by xenobiotic-metabolizing enzymes (XMEs) has been classified into phase I (functionalization) and phase II (conjugation) reactions. Cytochrome P450 (CYP) enzymes comprise 70–80% of all phase I XMEs. Although originally thought to be responsible for drug metabolism almost exclusively in the liver, it has now been realized that all XMEs participate in many crucial endogenous functions, probably in every eukaryotic cell and many prokaryotes. Of the 57 human CYP genes in 18 families, the members of the CYP1 to CYP4 families oxygenate thousands of xenobiotics (and endogenous substrates), whereas all members of the CYP5 family and higher principally metabolize endogenous substrates in a highly substrate-specific manner. CYP enzymes can cause tumour initiation through the formation of reactive intermediates (from exogenous and endogenous substrates). CYPs also participate in tumour initiation and progression through inflammation, other eicosanoid-mediated processes and other signal-transduction pathways. There is an interesting 'xenosensor' relationship that is not yet well understood among CYPs, XME receptors that regulate CYP expression and xenobiotic-related transporters (XRTs). Although several high-penetrance, predominantly monogenic (hPpM), traits including cancer have been correlated with various human CYP genes, the identification of a specific procarcinogen is rarely possible. Pharmacokinetic studies of several environmental toxicants in Cyp1 knockout mouse lines have shown that CYP1A1, CYP1A2 and CYP1B1 might be beneficial or detrimental — depending on their time-specific, organ-specific, tissue-specific and cell-type-specific expression. These new findings suggest that animal studies and human epidemiological studies might need to be revisited. Whereas oral drugs more commonly use the portal vein system (and first-pass elimination kinetics), we suggest that the lymphatic system might be more important in delivering the very hydrophobic oral polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs) to target tissues. This is especially relevant to clinical medicine, because oral exposure to these procarcinogens is the most predominant route. More focus on pharmacokinetic and pharmacodynamic studies of hydrophobic procarcinogens in animal models (and extrapolation to humans) is needed. A two-tiered model is proposed for the risk of developing cancer as a result of the environment. First, human inter-individual differences in the up-front hPpM traits, encoded by phase I genes, should have profound effects on a small (5–15%) proportion of any population who have no significant polymorphisms in downstream target genes. Second, all downstream targets of phase-I-mediated reactive intermediates can have their own important polymorphisms, always resulting in a unimodal gradient response.