CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

Abstract

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

A Robust and Fast/Multiplex Pharmacogenetics Assay to Simultaneously Analyze 17 Clinically Relevant Genetic Polymorphisms in CYP3A4, CYP3A5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, and VKORC1 Genes

“…We defined a panel of 17 genetic polymorphisms selected for their association with drug pharmacokinetics, drug response or when dosing recommendations were available in international databases [ 6 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The assay was designed to identify clinically relevant variants in genes coding for drug metabolizing enzymes from the CYP450 system and for the membrane transporter ATP-binding cassette 1 (ABCB1 or P-gp) since many drugs are substrate of this efflux pump.…”

Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity

“…Notably, patients carrying CYP3A4*22 had a 1.7 to five fold decreased CYP3A4 mRNA or protein expression level ( Elens et al, 2011 ; Wang et al, 2011 ; Wang and Sadee, 2016 ), explaining 12% of CYP3A4 activity variability ( Wang et al, 2011 ). Moreover, the reduced activity caused by the CYP3A4*22 allele was verified with several CYP3A substrates in vivo ( Elens et al, 2012 ; Elens et al, 2013a ; de Jonge et al, 2015 ), and its contribution to variability in CYP3A activity and its potential clinical usage were summarized by Elens et al and Mulder et al ( Elens et al, 2013b ; Mulder et al, 2021 ). While CYP3A4 is involved in the metabolism of many drugs, there are currently no clinical guidelines available that include CYP3A4 genetic variants.…”

Genome-wide microRNA profiles identify miR-107 as a top miRNA associating with expression of the CYP3As and other drug metabolizing cytochrome P450 enzymes in the liver

“…Many factors are known to influence the expression and function of the CYP3A enzymes. The genetic variant CYP3A4*22 (frequency 4%–8% in Whites and <1% in Blacks) reduces CYP3A4 expression 2–6-fold via affecting alternative splicing and transcription ( Wang et al, 2011 ; Wang and Sadee, 2016 ; Collins and Wang, 2020 ) and is considered the most clinically relevant genetic variant in CYP3A4, associating with many phenotypes related to CYP3A4 metabolism ( Mulder et al, 2021 ). Besides cis-acting genetic polymorphisms, the expression of the CYP3As is also regulated by trans-acting transcription factors (TFs), epigenetic modifications, and non-genetic factors ( Zanger and Schwab, 2013 ).…”