NGS testing for CYP gene and variation in drug responses



Among the most researched pharmacogenes is the CYP gene superfamily (Fukunaga et al., 2021), which influences drug-metabolising enzymes (DMEs) for phase I (enzymes responsible for reactions involving oxidation, reduction, and hydrolysis) and is thought to cause up to 60% of drug-induced toxicity (Maggo et al., 2016)

Four major phenotypes emerge concerning drug metabolism when considering polymorphisms in the CYP gene family; poor metaboliser, intermediate metaboliser, extensive metaboliser or ultra-rapid metaboliser.


Phase II enzymes (enzymes catalysing the conjugation reactions) polymorphisms contribute to further variation in drug responses. These include:

  • N-acetyl transferase type 2 (NAT2) - associated with isoniazid toxicity;

  • Thiopurine methyltransferases (TPMT) - associated with thiopurine toxicity;

  • Dihydropyrimidine dehydrogenase (DPD) - associated with 5-fluorouracil toxicity;

  • Uridine diphosphate-glucuronosyl transferases (UGT) - are associated with irinotecan toxicity.

Additional diversity in drug reactions can be influenced by drug transporter polymorphisms, which affect the distribution of the chemical components (Lauschke & Ingelman-Sundberg, 2019).


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Citations:


Fukunaga, K., Momozawa, Y., & Mushiroda, T. (2021). Update on next-generation sequencing of pharmacokinetics-related genes: development of the PKseq panel, a platform for amplicon sequencing of drug-metabolizing enzyme and drug transporter genes. Drug Metabolism and Pharmacokinetics, 37, 100370.


Lauschke, V. M., & Ingelman-Sundberg, M. (2019). Prediction of drug response and adverse drug reactions: from twin studies to next generation sequencing. European Journal of Pharmaceutical Sciences, 130, 65-77.


Maggo, S. D., Savage, R. L., & Kennedy, M. A. (2016). Impact of new genomic technologies on understanding adverse drug reactions. Clinical Pharmacokinetics, 55(4), 419-436.


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