Pharmacogenetics and Variability in Drug Response

The Cytochrome p450 enzymes belong to probably the largest gene superfamilies known. Comprising more than 6500 genes, there are 57 enzymes alone in humans, involved with the metabolism of endogenous and exogenous compounds. The original CYP450 gene is a very ancient one, tracing its origins back perhaps 2 billion years. All the known members of the gene superfamily probably arose from this ancient precursor through gene duplications etc.

This vast numbers of members is required at least in part for the metabolism of endogenous substrates, but it is likely that many have developed for the purpose of dealing with environmental toxicants which enter the body through mucosal barriers of the gut, and lungs, but also the skin. As the main route for the entry of environmental chemicals is via oral ingestion, the largest amount of p450 is found in the liver, as well as the intestinal linings.

The largest amount present in the liver belong to the 3A family. However, the abundance of the enzymes does not translate directly to the relatively importance of the enzyme with respect to the metabolism of pharmaceuticals. This is likely because the enzymic isoforms have evolved primarily for environmental chemicals, while pharmaceuticals as a subset of environmental chemicals, are chemicals with a very short and recent history.

The 3 most important families for pharmaceutical detoxification are CYP3A, CYP2D6 and CYP2C.

The recognition of CYP450's role in dealing with environmental chemicals allows us to anticipate that interactions between environmental chemicals (including dietary phytochemicals) and pharmaceuticals at the level of the CYP450 enzymes may be more prevalent than we have previously anticipated.