Pharmacogenomics

Pharmacogenomics deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with pharmacokinetics and pharmacodynamics. Pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficiency with minimal adverse effects.

Drug-metabolizing enzymes

Cytochrome P450: The most prevalent drug-metabolizing enzymes (DME) are the Cytochrome P450 (CYP) enzymes. The term Cytochrome P450 was coined by Omura and Sato in 1962 to describe the membrane-bound, heme-containing protein characterized by 450 nm spectral peak when complexed with carbon monoxide. The human CYP family consists of 57 genes, with 18 families and 44 subfamilies.

CYP2D6: It is also known as debrisoquine hydroxylase, CYP2D6 is the most well-known and extensively studied CYP gene.  It is a gene of great interest also due to its highly polymorphic nature, and involvement in a high number of medication metabolisms.

 CYP2C19:  Discovered in the early 1980s, CYP2C19 is the second most extensively studied and well understood gene in pharmacogenomics.  Over 28 genetic variants have been identified for CYP2C19, of which affects the metabolism of several classes of drugs, such as antidepressants and proton pump inhibitors.

CYP2C9: CYP2C9 constitutes the majority of the CYP2C subfamily, representing approximately 20% of the liver content. It is involved in the metabolism of approximately 10% of all drugs, which include medications with narrow therapeutic windows such as warfarin and tolbutamide.

CYP3A4 and CYP3A5: The CYP3A family is the most abundantly found in the liver, with CYP3A4 accounting for 29% of the liver content. These enzymes also cover between 40-50% of the current prescription drugs, with the CYP3A4 accounting for 40-45% of these medications.

VKORC1: The vitamin K epoxide reductase complex subunit 1 (VKORC1) is responsible for the pharmacodynamics of warfarin.  VKORC1 along with CYP2C9 are useful for identifying the risk of bleeding during warfarin administration. Warfarin works by inhibiting VKOR, which is encoded by the VKORC1 gene. Individuals with polymorphism in this have an affected response to warfarin treatment.

TPMT: Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines, thereby regulating the balance between cytotoxic thioguanine nucleotide and inactive metabolites in hematopoietic cells. TPMT is highly involved in 6-MP metabolism and TMPT activity and TPMT genotype is known to affect the risk of toxicity.

 

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