The Cytochrome P450 Enzymes of Hepatic Drug Metabolism: How are their Activities Assessed In Vivo, and what is their Clinical Relevance?
The cytochromes P450 comprise a superfamily of mixed function oxidases responsible for the oxidation of numerous endobiotics and thousands of xenobiotics. Though they are distributed in many organ systems, the hepatic cytochromes P450 are most prominent in both the detoxification and bioactivation of xenobiotics. They have been investigated intensively for over 30 years; however a systematic nomenclature did not evolve until it became clear that numerous isoforms existed. Based on similarities of amino acid sequences, the cytochrome P450 (CYP) enzymes have now been classified by family, subfamily, and isoform. As expression systems have been developed to assist in the determination of which isoforms mediate the oxidations of which substrates, it has become possible to model binding sites for some of the isoforms. This enterprise has been assisted by the determination of the amino acide sequence and the X-ray crystal structure of the bacterial cytochrome P450, P450(CAM). As the CYP enzymes play such a vital role in drug metabolism, and as the activities of various CYP isoforms have been implicated in cancer risk, there is a compelling need to develop methods for genotyping or phenotyping subpopulations with regard to CYP activity. It should be especially important to phenotype CYP activities in subpopulations anytime CYP enzyme activity can be regulated by environmental factors. A priori knowledge about CYP activity in various subpopulations (e.g., the aged, those with hepatic dysfunction, women, those occupationally exposed to certain environmental chemicals) will be helpful in predicting therapeutic outcomes for drugs whose elimination is CYP dependent. Additionally, cancer risk has been shown to correlate with various CYP activities, suggesting that a priori knowledge about select CYP activities may be useful in cancer risk assessment. Several noninvasive and minimally invasive strategies for phenotyping CYP activities have emerged in recent years. These procedures hold the promise of permitting investigators to phenotype select CYP isoform or subfamily activities within defined subpopulations through the use of endobiotic probes of CYP activity, xenobiotic probes of CYP activity, and noninvasive and minimally invasive measurements of those probes. This article reviews the CYP enzymes, the minimally invasive and noninvasive methods for characterizing their hepatic activities in humans in vivo, and the significance of being able to phenotype their activities in vivo.
Bachmann
Kenneth A.
KA