Variants in the CYP2B6 3′UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs

Burgess, Kimberly S.; Ipe, Joseph; Swart, Marelize; Metzger, Ingrid F.; Lu, Jessica Bo Li; Gufford, Brandon T.; Thong, Nancy; Desta, Zeruesenay; Gaedigk, Roger; Pearce, Robin E.; Gaedigk, Andrea; Liu, Yunlong; Skaar, Todd C.

doi:10.1002/cpt.892

Cited by 20 publications

(11 citation statements)

References 30 publications

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“…An increasing body of evidence demonstrates that small, noncoding RNAs, ranging between 20 and 24 nucleotides in length, provide an additional layer of regulation on the expression of drug metabolizing enzymes including CYPs [ 46 , 47 , 48 ] and that sequence variation in miRNA binding sites can perturb this mechanism as exemplified in vitro and in vivo by Burgess et al for the regulation of CYP2B6 expression [ 49 ]. Consistent with the finding that miRNA binding sites are often located in the 3’UTR region, the most prominent examples of CYP regulation by miRNAs involve binding sites in this region [ 49 , 50 , 51 , 52 , 53 ]. A bioinformatic search using 15 databases revealed that the 75 bp long 3’UTR of CYP2D6 contains a number of potential miRNA binding sites [ 47 ]; however, the author also indicated that this relatively small region does not harbor any known sequence variations that may interfere miRNA-mediated regulation.…”

Section: Genetic Factors Impacting Mrna and Protein Expression Levmentioning

confidence: 99%

Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

Gaedigk

Dinh

Jeong

et al. 2018

JPM

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117

122

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The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex CYP2D6 diplotype data into a patient’s phenotype to guide drug therapy and is at the core of all CYP2D6 gene/drug pair guidelines issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The AS, however, only explains a portion of the variability observed among individuals and ethnicities. In this review, we provide an overview of sources in addition to CYP2D6 genotype that contribute to the variability in CYP2D6-mediated drug metabolism and discuss other factors, genetic and non-genetic, that likely contribute to the observed variability in CYP2D6 enzymatic activity.

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Section: Genetic Factors Impacting Mrna and Protein Expression Levmentioning

confidence: 99%

Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

Gaedigk

Dinh

Jeong

et al. 2018

JPM

Self Cite

117

122

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“…The effect of a genetic variant (rs12979270), located in the 3′ UTR of the pharmacogene- CYP2B6, was shown to be statistically significant in HepaRG cells. A recent study shows that this variant, could explain part of the interindividual variability seen in the activity of this critical pharmacogene ( Burgess et al, 2017 ). These results demonstrate the potential of this assay to identify clinically relevant functional genetic variants.…”

Section: Resultsmentioning

confidence: 99%

PASSPORT-seq: A Novel High-Throughput Bioassay to Functionally Test Polymorphisms in Micro-RNA Target Sites

et al. 2018

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Next-generation sequencing (NGS) studies have identified large numbers of genetic variants that are predicted to alter miRNA–mRNA interactions. We developed a novel high-throughput bioassay, PASSPORT-seq, that can functionally test in parallel 100s of these variants in miRNA binding sites (mirSNPs). The results are highly reproducible across both technical and biological replicates. The utility of the bioassay was demonstrated by testing 100 mirSNPs in HEK293, HepG2, and HeLa cells. The results of several of the variants were validated in all three cell lines using traditional individual luciferase assays. Fifty-five mirSNPs were functional in at least one of three cell lines (FDR ≤ 0.05); 11, 36, and 27 of them were functional in HEK293, HepG2, and HeLa cells, respectively. Only four of the variants were functional in all three cell lines, which demonstrates the cell-type specific effects of mirSNPs and the importance of testing the mirSNPs in multiple cell lines. Using PASSPORT-seq, we functionally tested 111 variants in the 3′ UTR of 17 pharmacogenes that are predicted to alter miRNA regulation. Thirty-three of the variants tested were functional in at least one cell line.

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“…Studies profiling circulating miRNAs in liver diseases have shown that the expression of several miRNAs measured in plasma are upregulated or downregulated in liver diseases along with changes in CYP activity 18 . In vitro studies support a role of miRNAs in the regulation of CYP2B6 21 . In addition, exchange of miRNA between liver and blood may result in an association between circulating miRNA concentrations and hepatic CYP2B6 activity.…”

mentioning

confidence: 78%

Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity

Ipe

Metzger

et al. 2020

Clin Pharma and Therapeutics

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The CYP2B6 gene is highly polymorphic and its activity shows wide interindividual variability. However, substantial variability in CYP2B6 activity remains unexplained by the known CYP2B6 genetic variations. Circulating, cell‐free micro RNAs (miRNAs) may serve as biomarkers of hepatic enzyme activity. CYP2B6 activity in 72 healthy volunteers was determined using the disposition of efavirenz as a probe drug. Circulating miRNA expression was quantified from baseline plasma samples. A linear model consisting of the effects of miRNA expression, genotype‐determined metabolizer status, and demographic information was developed to predict CYP2B6 activity. Expression of 2,510 miRNAs were quantified out of which 7 miRNAs, together with the CYP2B6‐genotypic metabolizer status and demographics, was shown to be predictive markers for CYP2B6 activity. The reproducibility of the model was evaluated by cross‐validation. The average Pearson’s correlation (R) between the predicted and observed maximum plasma concentration (Cmax) ratios of efavirenz and its metabolite—8‐OH efavirenz using the linear model with all features (7 miRNA + metabolizer status + age + sex + race) was 0.6702. Similar results were also observed using area under the curve (AUC) ratios (Pearson correlation’s R = 0.6035). Thus, at least 36% (R2) of the variability of in vivo CYP2B6 activity was explained using this model. This is a significant improvement over the models using only the genotype‐based metabolizer status or the demographic information, which explained only 6% or less of the variability of in vivo CYP2B6 activity. Our results, therefore, demonstrate that circulating plasma miRNAs can be valuable biomarkers for in vivo CYP2B6 activity.

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Variants in the CYP2B6 3′UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs

Cited by 20 publications

References 30 publications

Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

PASSPORT-seq: A Novel High-Throughput Bioassay to Functionally Test Polymorphisms in Micro-RNA Target Sites

Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity

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