The observation that individuals respond differently to drugs due to their genetic basis has led to the genesis of pharmacogenetics and of late to pharmacogenomics. Nearly half a century has lapsed, after documenting the link between inheritance or ethnicity and aberrant drug responses. The differences in DNA sequences that alter the expression of function of proteins that are targeted by drugs can contribute significantly to variations in responses of individuals. This intersection of genetics and therapeutics' has the potential to yield a new set of molecular diagnostic tools that can be used for individualized and optimized drug therapy.
Following biochemical observations, supported by molecular genetics (recently cloning and characterization of genes involved) it is possible to identify the enzymes with their genes involved in metabolism. The differences in the genetic expression and reason for variation of genetic expression involved in the drug metabolizing system form the domains of pharmacogenomics. Enormous evidence has been accumulated regarding the genes responsible for drug metabolism, polymorphism in genes encoding drug transporter potential targets to alter drug responses (See Table 1 & Table 2).
| Table 1 Altered drug effects in humans due to genetic polymorphism |
| Drug (therapeutic category) | Drug response | enzyme / gene |
| NSAIDS | Enhanced anticoagulant effects | CYP2C9 |
| Antidepressants | Increased toxicity | CYP2D6 |
| Omeprazole | Altered response to peptic ulcer | CYP2C19 |
| Mercapropurine/Azathiopurine | Increased hematopioetic toxicity | Thiopurine methyl tranferase |
| Flurouracil (anticancer) | Increased neurotoxicity | Dihydropyrmidenases |
Table 2 Altered drug effects in humans due to polymorphism
of drug transporter (DT) and receptors (R) |
| Drug | Altered response | DT / R |
| Digoxin | Decreased digoxin activity | ABCB1( MDR-1) |
| HIV protease inhibitor | Decreased CD4 response | ABCB1(MDR-1) |
| Alubutol/terbutaline | Decreased bronco dilation | ß 2 adrenergic R |
| Atnalol / propranalol | Decreased cardiovascular response | ß 1 adrenergic R |
| Luekotriene R antagonist | Decreased forced expulsion volume | ALOX 5 |
| Fluoxetine | Decreased antidepressant effect | 5HT transporter |
Presently only monogenic traits that influence the drug response are best studied, sparing the much complex multiple genetic traits. One such example is that of thiopurine -S - methyl transferase and its influence on metabolism of drugs like mercaptopurine azathiopurine in the individuals who imbibe non-functional TRMT alleles. These drugs are used clinically for immunosuppresion and anticancer therapy.
In the individuals deficient in TPMT, mercaptopurine and azathiopurine accumulates in extremely toxic concentrations as TPMT nucleotides, which ultimately results into life threatening heamopioetic suppression. However identified TPMT individuals can be safely treated with adjusted s doses of the above drugs which amounts to 5 -10% of conventional doses.
Clinical diagnostic kits for detection of SNP in the human TPMT gene are available commercially, which can be utilized for identification of the individuals. There is growing list of polymorphisms found in genes encoding drug metabolizing enzymes, drug transporters, drug targets and as well as disease modifying genes linked to drug effects. All these data is based on studies representing SNP's, where as most of the drug effects and treatment outcomes are resultant of multiple genes, which hints at polygenic approach to be most appropriate. The pharmcogenomics aims at determining the drug responses as a result of multiple gene interplay capitalizing on information from human genome project and on advanced technologies like ultra high throughput sequencing of DNA and protein, microarray and bioinformatics.
As it would take enormous efforts and resources to sequence entire genome of every individual, it is very easy and cost effective to resolve candidate gene or candidate pathway approach. For example in candidate gene approch, the variability to drug response by individuals in a population is dependent on the expression of drug metabolizing enzyme. After earmarking of the enzyme most important for metabolism of the drug, the gene coding for that enzyme is identified. It is further used to find out the drug metabolizing capacity of the individual by targeting the candidate gene.
For example many individuals show variation in pharmcodynamic profile to antihypertensive drug debriisoquine and oxytocic drug spartiene. This observation led to the studies of human livers to identify and isolation of the enzymes and their respective genes. In the pathways of gene approch, it is the network of genes acting together is studied than single gene. For example high oxidative capacity of cytochrome P450 coupled with low conjugating capacity acting in a sequence. In such a situation there could be accumulation of huge amounts of oxidative metabolites, which could be toxic to the liver.
Alternatively, polymorphisms in genes on common pathways may set off each other so that deficiency in one of the gene expression/function becoming obscure. For example black people are reported to have high polymorphism's associated with expression of CYP3AS compared to white people. Where as white people have high polymorphs for P-glycoprotein, cell drug expulsion pump. Thus polymorphs of metabolizing enzymes and drug expulsion protein counter balance each other and mask the overall population variability in pharmacodynamics.
In future, it seems advancement in technologies will bring down the cost and complexity of the pharmcogenomics tests and would become the mandatory for therapeutics of all diseases. It would than be possible to establish definitive polygenic models for optimizing the drug therapy. As there are millions of human genomic polymorphism's reported, the best way possible is to take consideration of human genomic polymorphisms in planing of clinical trials.
The studies should also include comprehensive and rigorous pharmacogenomic aspects. Incorporation of genetic tests in the protocols of clinical trials may become mandatory in future. If the mode prescription of medicine is to change from empirical approch to evidence based therapy there is a hope here. Utmost cautions to be assured to the individuals regarding the avoidance of misuse of genetic information. The cost effectiveness to be viewed as a preventive of wrong medication and the optimizing the individualized dose.
-- The author is with Pharmacy group, Birla Institute of Technology and Science, Pilani