The Experts for Comprehensive, Convenient Personalized Health!
The Experts for Comprehensive, Convenient Personalized Health!
Pharmacogenomics (PGx) is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology and genomics to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Below are common pharmacogenes and their clinical applications.
Phase I metabolism involve a variety of reactions (eg., oxidation, dealkylation, reduction and hydrolysis) that are catalyzed by three major enzyme superfamilies: (1) cytochrome P450s (CYPs), (2) flavin-containing monooxygenases, (3) epoxide hydrolases (Gonzales, 2022; Susa,2022). Whereas phase II modifications primarily involve conjugation reactions that couple the drug molecule to various chemical structures (eg., sulfate, glucuronic acid, glutathione, acetyl, and methyl groups) and are largely catalyzed by various transferase enzymes: glutathione S transferases (GSTs), thiopurine-S-methyltransferase (TPMT), UDP-glucuronosyltransferases (UGTs), N-acetyl-transferases (NATs), and NADH quinone oxidases (Yiannakopoulou, et al. 2013). Following phase II metabolism drugs can undergo further modification and excretion during phase III metabolism, a process that usually involves ATP-dependent transport via an ABC or SLC transport protein (Phang, et al. 2021). Table 1 provides a summary of important pharmacogenes of interest, their associated substrates, and drug effects that have been linked to polymorphisms associated with these pharmacogenes.
The CYP superfamily of enzymes are responsible for metabolizing the majority of therapeutic drugs used in treating various disease states (Gonzalez, et al, 2022). Figure 1 provides an overview of major CYP450 enzymes involved in drug metabolism and their associated percent contributions. In humans, genomic sequencing has identified 57 functional CYP genes as well as 58 pseudogenes (nonfunctional gene segments resembling functional genes) (Nelson, et al. 2004). CYP genes are categorized into 18 families and 44 subfamilies based on similarities in the corresponding amino acid sequences of their enzyme products (Nebert and Russell, 2002). CYP nomenclature consists of the CYP root followed by a numerical family designation, letter subfamily designation, and ends with a number denoting the specific gene (eg., CYP2D6: family 2, subfamily D, gene number 6) (Gonzalez, et al, 2022). Notably, only 12 enzymes belonging to the CYP1, 2, and 3 families play a major role in the metabolism of drugs used in the clinical setting (Zanger, 2013; Tornio, 2018). Genetic polymorphisms can explain a large proportion of variability observed with certain CYP enzymes, including CYP2C9, CYP2C19, and CYP2D6; however, other CYP enzymes, such as CYP1A2 and CYP3A4 are less impacted by gene variants. The following will discuss genetic polymorphisms of major CYP enzymes, observed differences in allelic frequencies across ethnically diverse subgroups, and the associated impact on clinical drug response.
Following phase I metabolism, resulting products undergo further metabolism via phase II conjugation reactions. Enzymes responsible for catalyzing phase II reactions are categorized according to the type of conjugation reaction: (1) glucuronidation via UDP-glucuronosyltransferases (UGTs); (2) sulfonation via sulfotransferases (SULT); (3) acetylation, N-acetyltransferases (NATs); (4) glutathione conjugation, glutathione-S-transferases (GSTs); (5) amino acid conjugation, and (6) methylation, methyltransferases (MTs) (Gonzales, 2022; Murray, 2013). The two most notable pharmacogenes of interest include UGT1A1, which encodes the UDP-glucuronosyltransferase family 1 member A1 enzyme and TPMT, which encodes the thiopurine methyltransferase enzyme (UGT1A1_MedlinePlus, 2022; TPMT_MedlinePlus, 2022). Figure 2 provides a breakdown of phase II drug metabolizing enzymes and their overall contributing percentages with regard to phase II drug metabolism.