DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in fluoropyrimidine (fluorouracil, capecitabine) catabolism. The less residual DPD activity a genotype confers, the greater the drug exposure and the risk of severe, potentially fatal toxicity.
TPMT encodes thiopurine S-methyltransferase, which inactivates thiopurines (azathioprine, mercaptopurine). Reduced-function or no-function alleles divert more drug to cytotoxic thioguanine nucleotides, raising the risk of severe, potentially life-threatening myelosuppression, greatest with biallelic deficiency.
NUDT15 encodes nudix hydrolase 15, which dephosphorylates active thiopurine nucleotides before their incorporation into DNA. Inherited no-function variants let these metabolites accumulate and increase the risk of severe thiopurine toxicity; TPMT and NUDT15 contribute independently to thiopurine metabolism, and both genes are considered jointly when assessing the risk of thiopurine toxicity.
CYP2C8 contributes to the metabolism of the taxane paclitaxel. Certain CYP2C8 variants have been associated with altered drug clearance and may influence the risk of taxane-induced peripheral neuropathy, although the clinical relevance of these associations remains incompletely understood.
UGT1A1 encodes UDP-glucuronosyltransferase 1A1, which converts SN-38, the active metabolite of irinotecan, into an inactive form. Reduced-function genotypes may result in increased SN-38 exposure and are associated with an increased risk of treatment-related neutropenia and diarrhoea, particularly at higher irinotecan doses.
CYP2D6 contributes to the conversion of tamoxifen to its active metabolite endoxifen. Reduced-function and no-function genotypes are associated with lower endoxifen concentrations and may contribute to interindividual differences in treatment response.
As with other pharmacogenetic markers, concomitant medication and other non-genetic factors may alter enzyme activity and lead to differences between the genotype-predicted and observed phenotype.
