Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity.

If you need an accessible version of this item, please submit a remediation request.
Date
2021-02
Language
English
Embargo Lift Date
Department
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
Wiley
Abstract

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 (C(max) ) 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% (R(2) ) 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.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Ipe, J., Li, R., Metzger, I. F., Bo Li Lu, J., Gufford, B. T., Desta, Z., Liu, Y., & Skaar, T. C. (2021). Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity. Clinical Pharmacology and Therapeutics, 109(2), 485–493. https://doi.org/10.1002/cpt.2018
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Source
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Full Text Available at
This item is under embargo {{howLong}}