Effects of xenobiotics and peroxisome proliferator-activated receptor-α on the human UDPglucose dehydrogenase gene expression

Abstract

During drug metabolism, UDPglucuronate, a product of the reaction catalyzed by the enzyme UDPglucose dehydrogenase (UGDH), is conjugated with the metabolites to facilitate their elimination. So far, it is not known whether xenobiotics can modulate the UGDH gene expression. This question was tested by treating the human hepatoma cells HepG2 with several medicinal compounds and the UGDH gene expression analyzed by using real-time PCR. Both eugenol and rifampicin showed activation of the gene expression. Piperine showed slight down-regulation of the UGDH gene expression, whereas no effect was observed with acetaminophen treatment. Through promoter-reporter gene assays, we found that rifampicin showed multiple-folds activation of a 1.23-kb UGDH promoter construct, the region likely to respond to rifampicin treatment is located within the range -632 to -1,050. A bioinformatics search for xenobiotic response element in this region has predicted a binding motif for the peroxisome proliferator-activated receptor-alpha(PPARalpha) at position -1,003. A mutation at the predicted PPAR recognizing motif eliminated normal suppression as well as the rifampicin activation effect on the UGDH promoter activity. Cotransfection with the PPARalpha and retinoid X receptor-alpha expression vectors and subsequent treatment with the PPARalpha agonist led to the suppression of the UGDH promoter activity either in the presence or absence of rifampicin. Our study, for the first time, shows the UGDH gene to be under xenobiotic regulation and delineates a motif responsible for rifampicin response and transcriptional repression of the UGDH gene.