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OV‐A‐2
Author(s) -
Cascorbi I.,
Remmler C.,
Haenisch S.,
Hecker U.,
Siegmund W.
Publication year - 2006
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.2005.12.123
Subject(s) - genotype , rifampicin , biology , messenger rna , basal (medicine) , pharmacology , microbiology and biotechnology , medicine , gene expression , gene , endocrinology , antibiotics , genetics , insulin
BACKGROUND The human UDP‐glucuronosyltransferase 1A1 (UGT1A1) is a major phase‐II drug metabolizing enzyme, catalyzing conjugation of e.g. bilirubin with glucuronic acid. It is inducible by rifampicin and is subject of hereditary variability due to a polymorphic TATA‐box in the 5'‐region of the UGT1A1 gene (UGT1A1*28). We aimed to investigate the impact of the genotype on UGT1A1 mRNA expression after rifampicin pre‐treatment. METHODS 15 healthy Caucasian volunteers were included. The UGT1A1 TA repeat polymorphisms was determined from leukocyte DNA by capillary electrophoresis. Duodenal biopsies were obtained before and after 8 days of rifampicin treatment (600 mg/d p.o.). mRNA was isolated from duodenal biopsies, quantified by real‐time RT‐PCR and compared to 18S rRNA. RESULTS The basal UGT1A1 mRNA/18S rRNA expression level differed marginally (p=0.19). However, among 6 carriers with TA6/6 and 6 with TA6/7 genotype, ratios were about 5.1‐ or 3.7‐fold elevated after rifampicin treatment compared to the basal level (p=0.028; 0.028 respectively). In contrast, UGT1A1 expression in TA7/7 homozygotes was not influenced by rifampicin (p=0.66). CONCLUSION PXR‐mediated UGT1A1 induction is genotype dependent, presumably caused by weakened DNA‐protein interaction by an additional TA‐repeat (TA7/7). Consequently, the extent of drug‐interactions may vary inter‐individually. Clinical Pharmacology & Therapeutics (2005) 79 , P34–P34; doi: 10.1016/j.clpt.2005.12.123