Developmental aspects of human hepatic drug glucuronidation in young children and adults

Abstract

Background and aims: The liver represents one of the major sites of human glucuronidation. Many therapeutic drugs are substrates for UDP-glucuronosyltransferases (UGT) leading to the formation of usually inactive glucuronides. Hepatic glucuronidation undergoes significant changes during fetal and neonatal development requiring age adapted drug therapy. Regulation of individual UGT genes during hepatic development has not been defined. Subjects and methods: Expression of 13 UGT genes and glucuronidation activities were analysed in 16 paediatric liver samples (aged 7-24 months), two fetal samples, and 12 adult liver samples (aged 25-75 years) using duplex reverse transcription-polymerase chain reaction, western blot, and specific catalytic UGT activity assays. Results: No UGT transcripts were detected in fetal liver at 20 weeks' gestation. In contrast, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, and UGT2B15 transcripts were present without variation in all 28 hepatic samples after six months of age. Significantly lower expression of UGT1A9 and UGT2B4 mRNA was identified in paediatric liver. Hepatic glucuronidation activity in children aged 13-24 months was found to be lower than in adults for ibuprofen (24-fold), amitriptyline (16-fold), 4-tert-butylphenol (40-fold), estrone (15-fold), and buprenorphine (12-fold). Conclusions: An early phase characterised by the appearance of UGT gene transcripts and a later phase characterised by upregulation of UGT expression is demonstrated during human hepatic development. The differential regulation of UGT1A9 and UGT2B4 expression extends beyond two years of age and is capable of influencing hepatic glucuronidation of common therapeutic drugs in children. The development of hepatic UGT activities is significant for paediatric drug therapy and the prevention of adverse drug effects.

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

“…Physiologic neonatal jaundice is associated with both an increased rate of erythrocyte turnover (41) and low levels of bilirubin UDP glucuronosyltransferase activity (42)(43)(44). The results described here suggest that decreased expression of CAR may account for the apparent failure of expression of UGT1A1 and other components of the pathway to increase in response to the increased demand.…”

Increased UGT1A3 and UGT1A7 Expression is Associated with Pancreatic Cancer

“…Five single nucleotide polymorphisms of the UGT1A7 gene were identified. UGT1A7 gene defining three polymorphic UGT1A7 alleles (UGT1A7 *2 , UGT1A7 *3 and UGT1A7 *4 ) (Strassburg et al, 2002b). The UGT1A7 *3 allele with low mutagen detoxification activity was identified as a risk factor for cancers of the pancreas (Ockenga et al, 2003) and colorectal (Tang et al, 2005).…”

Phase II Drug Metabolism

“…Cytosolic SULTs constitute the second group of sulfotransferases and play a major role in conjugation of a broad spectrum of xenobiotics including environmental chemicals, natural compounds, drugs as well as endogenous compounds such as steroid hormones, iodothyronines, catecholamines, eicosanoids, retinol or vitamin D (Glatt & Meinl, 2004). Moreover, cytosolic SULTs are presumed to play a crucial role in the detoxification processes occurring in the developing human fetus since no UGTs transcripts have been detected in fetal liver at 20 weeks of gestation (Strassburg et al, 2002). Sulfonation is generally described as a detoxification pathway for many xenobiotics.…”