Abstract
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
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