Premium
Genetic determinants of UGT1A1 inducibility
Author(s) -
Ramirez J.,
Innocenti F.,
Komoroski B. J.,
Mirkov S.,
Yoder Graber A.,
Fackenthal D.,
Das S.,
Schuetz E. G.,
Strom S. C.,
Ratain M. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.096
Subject(s) - indel , single nucleotide polymorphism , basal (medicine) , snp , microbiology and biotechnology , medicine , allele , biology , phenotype , endocrinology , chemistry , genetics , gene , genotype , insulin
Background UGT1A1 is induced by phenobarbital (PB). This study investigates whether the TATA box indel and two SNPs in the PBREM region are associated with the variability in the inductive phenotype. Methods Human hepatocytes (n=36) were incubated with 2 mM PB (48 h) followed by 5 μM SN‐38 (1 h), a UGT1A1 probe. SN‐38 glucuronide (SN‐38G) in the cell media was measured by HPLC. Three UGT1A1 variants (−53(TA) 6>7 , −3156G>A and −3279T>G) were genotyped. Samples were considered to be induced if the SN‐38G levels in PB‐treated cells increased by at least 25% when compared to untreated cells, and P <0.05 (unpaired t‐test). Results Significant UGT1A1 induction was observed in 81% of the cultures (fold‐induction=1.7±0.4, mean±SD). The SN‐38G concentrations in the basal and induced states were highly correlated (r=0.94, P <0.0001). The allele frequencies were not significantly different between induced (n=24) and non‐induced cases (n=6) ( 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 <0.05). No association was found with the −3279T>G SNP ( P >0.05). The fold‐induction was not associated with any variants ( P >0.05). Conclusions The indel at −53 affects the basal phenotype and seems to limit the hepatocyte capability of maximal induction after PB. However, variants at −53, −3156 and −3279 are not associated with variability in UGT1A1 inducibility. Clinical Pharmacology & Therapeutics (2005) 77 , P25–P25; doi: 10.1016/j.clpt.2004.11.096