CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Takuto Takahashi; Angela R. Smith; Pamala A. Jacobson; Abeer F. Alharbi; James Fisher; Nathan T. Rubin; Mark N. Kirstein

doi:10.5414/cp203920

CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Takuto Takahashi, Angela R. Smith, Pamala A. Jacobson, Abeer F. Alharbi, James Fisher, Nathan T. Rubin, Mark N. Kirstein

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

Original language	English (US)
Pages (from-to)	442-446
Number of pages	5
Journal	International Journal of Clinical Pharmacology and Therapeutics
Volume	59
Issue number	6
DOIs	https://doi.org/10.5414/cp203920
State	Published - Jun 1 2021

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Publisher Copyright:
© 2021 Dustri-Verlag Dr. Karl Feistle. All rights reserved.

Keywords

CYP51A
Hepatotoxicity
Pharmacogenomics
Voriconazole

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10.5414/cp203920

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title = "CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant",

abstract = "Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).",

keywords = "CYP51A, Hepatotoxicity, Pharmacogenomics, Voriconazole",

author = "Takuto Takahashi and Smith, {Angela R.} and Jacobson, {Pamala A.} and Alharbi, {Abeer F.} and James Fisher and Rubin, {Nathan T.} and Kirstein, {Mark N.}",

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TY - JOUR

T1 - CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

AU - Takahashi, Takuto

AU - Smith, Angela R.

AU - Jacobson, Pamala A.

AU - Alharbi, Abeer F.

AU - Fisher, James

AU - Rubin, Nathan T.

AU - Kirstein, Mark N.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

AB - Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

KW - CYP51A

KW - Hepatotoxicity

KW - Pharmacogenomics

KW - Voriconazole

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DO - 10.5414/cp203920

M3 - Article

C2 - 33560212

AN - SCOPUS:85106936167

SN - 0946-1965

VL - 59

SP - 442

EP - 446

JO - International Journal of Clinical Pharmacology and Therapeutics

JF - International Journal of Clinical Pharmacology and Therapeutics

IS - 6

ER -

CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Abstract

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