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Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes.

Abstract：

:UGT1A1 is induced by phenobarbital. We investigated whether three common UGT1A1 variants are associated with the variability in UGT1A1 inducibility. Human hepatocytes were incubated with 2 mM phenobarbital for 2 and 6 days followed by 5 microM SN-38 (1 h), a UGT1A1 probe. SN-38 glucuronidation in the cell media was measured by high-performance liquid chromatography. Three UGT1A1 promoter variants [-53(TA)(6>7), -3156G > A and -3279T > G] were genotyped. Significant induction of UGT1A1 catalytic activity was observed in 82% and 100% of the cultures treated with phenobarbital for 2 days (median fold-induction = 1.6, range 1.3-2.8; n = 28) and 6 days (median fold-induction = 2.8, range 1.6-6.4; n = 16), respectively. After 2 days of treatment, a negative correlation was observed between the UGT1A1 basal activities and the fold-induction (Spearman r = -0.52, P < 0.005). By contrast, the UGT1A1 activities in the basal and induced states were highly correlated (Spearman r = 0.95, P < 0.0001). Similar results were observed after 6 days of treatment. The allele frequencies were not significantly different between induced (n = 22) and non-induced preparations (n = 6) (P > 0.05). The fold-induction was not associated with any variants (P > 0.05). The basal and induced activities were correlated with -53(TA)(6>7) (and with -3156G > A due to almost complete linkage with the -53 indel) (P = 0.001). No association was found with the -3279T > G single nucleotide polymorphism (P > 0.05). The indel at -53 affects the basal phenotype and appears to limit the hepatocyte capability of maximal induction after phenobarbital. However, variants at -53, -3156 and -3279 are not associated with variability in UGT1A1 inducibility.

journal_name

Pharmacogenet Genomics

journal_title

Pharmacogenetics and genomics

authors

Ramírez J,Komoroski BJ,Mirkov S,Graber AY,Fackenthal DL,Schuetz EG,Das S,Ratain MJ,Innocenti F,Strom SC

doi

10.1097/01.fpc.0000182784.77630.48

keywords:

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

79-86

issue

eissn

1744-6872

issn

1744-6880

pii

01213011-200602000-00002

journal_volume

pub_type

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Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes.