Relation between Pharmacology & Genetics

Pharmacology & Genetics
During the last 5 years, the genomes of humans, mice, and many other organisms have been
decoded in considerable detail. This has opened the door to a remarkable range of new approaches
to research and treatment. It has been known for centuries that certain diseases are inherited, and we
now understand that individuals with such diseases have a heritable abnormality in their DNA. It is
now possible in the case of some inherited diseases to define exactly which DNA base pairs are
anomalous and in which chromosome they appear. In a small number of animal models of such
diseases, it has been possible to correct the abnormality by "gene therapy," ie, insertion of an
appropriate "healthy" gene into somatic cells. Human somatic cell gene therapy has been attempted,
but the technical difficulties are great.
Studies of a newly discovered receptor or endogenous ligand are often confounded by incomplete
knowledge of the exact role of that receptor or ligand. One of the most powerful of the new genetic
techniques is the ability to breed animals (usually mice) in which the gene for the receptor or its
endogenous ligand has been "knocked out," ie, mutated so that the gene product is absent or
nonfunctional. Homozygous "knockout" mice will usually have complete suppression of that
function, while heterozygous animals will usually have partial suppression. Observation of the
behavior, biochemistry, and physiology of the knockout mice will often define the role of the
missing gene product very clearly. When the products of a particular gene are so essential that even
heterozygotes do not survive to birth, it is sometimes possible to breed "knockdown" versions with
only limited suppression of function. Conversely, "knockin" mice have been bred that overexpress
certain receptors of interest.
Some patients respond to certain drugs with greater than usual sensitivity. (Such variations are
discussed in Chapter 4: Drug Biotransformation.) It is now clear that such increased sensitivity is
often due to a very small genetic modification that results in decreased activity of a particular
enzyme responsible for eliminating that drug. Pharmacogenomics (or pharmacogenetics) is the
study of the genetic variations that cause individual differences in drug response. Future clinicians
may screen every patient for a variety of such differences before prescribing a drug.