C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation

Maki Goto, Satohiro Masuda, Hideyuki Saito, Shinji Uemoto, Tetsuya Kiuchi, Koichi Tanaka, Ken Ichi Inui

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/ C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.

Original languageEnglish
Pages (from-to)451-457
Number of pages7
JournalPharmacogenetics
Volume12
Issue number6
DOIs
Publication statusPublished - Aug 1 2002
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Enterocytes
Living Donors
P-Glycoprotein
Liver Transplantation
Tacrolimus
Genes
MDR Genes
Messenger RNA
Genetic Polymorphisms
Gene Frequency
Cytochrome P-450 Enzyme System
Biological Availability
Polymerase Chain Reaction
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. / Goto, Maki; Masuda, Satohiro; Saito, Hideyuki; Uemoto, Shinji; Kiuchi, Tetsuya; Tanaka, Koichi; Inui, Ken Ichi.

In: Pharmacogenetics, Vol. 12, No. 6, 01.08.2002, p. 451-457.

Research output: Contribution to journalArticle

Goto, Maki ; Masuda, Satohiro ; Saito, Hideyuki ; Uemoto, Shinji ; Kiuchi, Tetsuya ; Tanaka, Koichi ; Inui, Ken Ichi. / C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. In: Pharmacogenetics. 2002 ; Vol. 12, No. 6. pp. 451-457.
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AU - Uemoto, Shinji

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AU - Inui, Ken Ichi

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AB - The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/ C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.

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