Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation

Masakatsu Yanagimachi, Takuya Naruto, Reo Tanoshima, Hiromi Kato, Tomoko Yokosuka, Ryosuke Kajiwara, Hisaki Fujii, Fumiko Tanaka, Hiroaki Goto, Tatsuhiko Yagihashi, Kenjiro Kosaki, Shumpei Yokota

Research output: Contribution to journalArticle

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Abstract

Background: One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.Methods: The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.Results: Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).Conclusion: The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs.

Original languageEnglish
Pages (from-to)855-861
Number of pages7
JournalClinical Transplantation
Volume24
Issue number6
DOIs
Publication statusPublished - 2010 Nov

Fingerprint

Cytochrome P-450 CYP3A
Hematopoietic Stem Cell Transplantation
Tacrolimus
Genes
P-Glycoprotein
Cyclosporine
Genotype
Renal Hypertension
Calcineurin Inhibitors
Logistic Models
Alleles
Regression Analysis
Hypertension
Kidney

Keywords

  • ABCB1
  • Calcineurin inhibitor
  • CYP3A5
  • Neurotoxicity
  • Polymorphism

ASJC Scopus subject areas

  • Transplantation

Cite this

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. / Yanagimachi, Masakatsu; Naruto, Takuya; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Hiroaki; Yagihashi, Tatsuhiko; Kosaki, Kenjiro; Yokota, Shumpei.

In: Clinical Transplantation, Vol. 24, No. 6, 11.2010, p. 855-861.

Research output: Contribution to journalArticle

Yanagimachi, M, Naruto, T, Tanoshima, R, Kato, H, Yokosuka, T, Kajiwara, R, Fujii, H, Tanaka, F, Goto, H, Yagihashi, T, Kosaki, K & Yokota, S 2010, 'Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation', Clinical Transplantation, vol. 24, no. 6, pp. 855-861. https://doi.org/10.1111/j.1399-0012.2009.01181.x
Yanagimachi, Masakatsu ; Naruto, Takuya ; Tanoshima, Reo ; Kato, Hiromi ; Yokosuka, Tomoko ; Kajiwara, Ryosuke ; Fujii, Hisaki ; Tanaka, Fumiko ; Goto, Hiroaki ; Yagihashi, Tatsuhiko ; Kosaki, Kenjiro ; Yokota, Shumpei. / Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. In: Clinical Transplantation. 2010 ; Vol. 24, No. 6. pp. 855-861.
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T1 - Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation

AU - Yanagimachi, Masakatsu

AU - Naruto, Takuya

AU - Tanoshima, Reo

AU - Kato, Hiromi

AU - Yokosuka, Tomoko

AU - Kajiwara, Ryosuke

AU - Fujii, Hisaki

AU - Tanaka, Fumiko

AU - Goto, Hiroaki

AU - Yagihashi, Tatsuhiko

AU - Kosaki, Kenjiro

AU - Yokota, Shumpei

PY - 2010/11

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N2 - Background: One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.Methods: The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.Results: Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).Conclusion: The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs.

AB - Background: One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.Methods: The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.Results: Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).Conclusion: The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs.

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