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Assessment of CYP2D6 gene expression in liver tissue: Variability in CYP2D6 mRNA levels within genotype-predicted metabolizer phenotype groups

Year: 2025

Type: article

Abstract: Pharmacogenetic (PGx) testing can be used to help guide drug therapy and decrease or avoid the risk of adverse drug reactions. CYP2D6 is an important pharmacogene in pharmacogenomics testing panels. However, phenoconversion, whereby an individual's ability to metabolize a drug does not match the genotype-predicted metabolizer status, is a confounding factor to the accurate application of PGx testing results to patient care. To address this issue, CYP2D6 expression between and within genotype-predicted CYP2D6 metabolizer phenotype groups was compared using WGS and RNA-Seq data from 134 normal liver tissue donors obtained from the GTEx program. Wide variability in CYP2D6 mRNA levels was observed within metabolizer phenotype groups. The median expression level for ultrarapid metabolizers (UMs) was 738.9 TPM (transcripts per million; 196.8–778.9 TPM), 212.5 TPM (32.1–666.5 TPM) for normal metabolizers (NMs), 219.6 TPM for intermediate metabolizers (IMs) (22–389.8 TPM), and 121.2 TPM for poor metabolizers (PMs) (9.3–298.2 TPM). The PM and UM phenotypes were significant predictors of CYP2D6 expression ( p = 0.0004 and p = 0.019, respectively). Interestingly, expression of the gene encoding human serum albumin ( ALB ) was also a significant predictor of CYP2D6 expression ( p = 0.0003). Data from 50 patients with hepatocellular carcinoma obtained from the TCGA program showed no significant difference in expression between tumor tissue (median = 119.7 TPM, range 0.16–817.7 TPM) and normal matched tissue (median = 143.3 TPM, range 26.2–810.7 TPM). Transcriptional regulation of CYP2D6 expression may contribute to differences in drug response and risk for CYP2D6 phenoconversion. Efforts to understand the role of gene expression to predict CYP2D6 phenoconversion may inform the use of PGx testing in the clinical setting. • The association between adverse drug reactions and genetic variants of CYP2D6 is well-known. • Pharmacogenetic testing cannot address differences in drug response among patients with the same CYP2D6 metabolizer phenotype. • This study demonstrates the variability of CYP2D6 mRNA levels within CYP2D6 metabolizer phenotype groups. • Variability in CYP2 D6 gene expression may contribute to individual differences in drug response. • Biomarkers correlated with CYP2D6 gene expression may improve the predictive value of pharmacogenetic testing.

Source: Chemico-Biological Interactions

DOI: 10.1016/j.cbi.2025.111526