Cytochrome P450, xenobiotic-metabolizing expression systems

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

In vitro systems containing human xenobiotic-metabolizing enzymes can provide qualitative data, such as the human metabolites which may be produced in vivo and which enzymes are capable of producing these metabolites. When comparing quantitative aspects of metabolism among different cytochrome P450 forms in a cDNA expression system, the data can be interpreted in two contexts ... 

The need to consider all the enzymes which metabolize a xenobiotic underscores the importance of having a comprehensive set of enzymes expressed in the heterologous system. For the purposes of this discussion, only cytochrome P450 substrates will be considered. For the cytochrome P450 system, the individual enzymes are better characterized (at this time) than with other. Phase II enzymes. 

The cDNA expression systems can be used to address questions such as can human enzymes metabolize a xenobiotic What are the metabolites Can human enzymes activate a protoxin In order to adequately support a negative conclusion it is obvious that the range of cytochrome P450 enzymes examined needs to be as comprehensive as possible. 

The field of xenobiotic metabolism is rich with a myriad of different, often competing, pathways of metabolism. Efforts at cDNA expression have only begun to develop comprehensive systems for the analysis of all Phase I and all Phase II enzymes. A comprehensive set of human cytochrome P450 and Phase II enzymes is not available in the context of a single host cell type, but given the rate of progress, we can look forward to nearly complete systems in the near future. 

---