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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3′UTR may explain variable drug response by altering microRNA regulation. Five 3′UTR variants were associated with significantly altered efavirenz AUC0-48 (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with a 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA (P < 0.05)). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing an 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (P=0.0035). Our results show that a 3′UTR variant contributes to variability in CYP2B6 activity.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
DOIs
StateAccepted/In press - 2017

Fingerprint

MicroRNAs
efavirenz
Alleles
Binding Sites
Luciferases
Cytochrome P-450 CYP2B6
In Vitro Techniques
Healthy Volunteers
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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; Gufford, Brandon T.; Thong, Nancy; Desta, Zeruesenay; Gaedigk, Roger; Pearce, Robin E.; Gaedigk, Andrea; Liu, Yunlong; Skaar, Todd.

In: Clinical Pharmacology and Therapeutics, 2017.

Research output: Contribution to journalArticle

Burgess, Kimberly S. ; Ipe, Joseph ; Swart, Marelize ; Metzger, Ingrid F. ; Lu, Jessica ; Gufford, Brandon T. ; Thong, Nancy ; Desta, Zeruesenay ; Gaedigk, Roger ; Pearce, Robin E. ; Gaedigk, Andrea ; Liu, Yunlong ; Skaar, Todd. / Variants in the CYP2B6 3′UTR Alter In Vitro and In Vivo CYP2B6 Activity : Potential Role of MicroRNAs. In: Clinical Pharmacology and Therapeutics. 2017.
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AU - Liu, Yunlong

AU - Skaar, Todd

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