Cytochrome P450, xenobiotic-metabolizing system

During periods of immune system response, for example, at times of infectious disease, cytochrome P450-dependent metabolism of xenobiotics is reduced. This effect is attributed to the production of interferon by the immune system as it responds to a challenge. Human interferon has been shown to suppress the metabolism of benzo [a] pyrene in laboratory animalsJ19 ... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

The cytochrome P450 system is the principal enzyme system for the metabolism of lipophilic xenobiotics. It is a heme-containing, membrane-bound, multi-enzyme system which is present in many tissues in vivo but is present at the highest level in liver. A coenzyme, cytochrome P450 NADPH oxidoreductase (OR), is essential for P450 catalytic function and cytochrome bs may stimulate catalytic activities of some enzymes. In human liver, it is estimated that there are 15-20 different xenobiotic-metabolizing cytochrome P450 forms. A standard nomenclature, based on relatedness of the amino acid sequences, has been developed (Nelson et al., 1993). The most recent... 

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. 

Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds. 

---