Molecular basis of bilirubin UDP-glucuronosyltransferase induction in spontaneously diabetic rats, acetone-treated rats and starved rats

Abstract

The co-ordinated induction of several hepatic drug-metabolizing enzymes is a common feature in the regulation of drug biotransformation under normal and pathological conditions. In the present study the activity and expression of bilirubin UDP-glucuronosyltransferase (UGT1A1) were investigated in livers of BioBreeding/Worcester diabetic, fasted and acetone-treated rats. Bilirubin glucuronidation was stimulated by all three treatments; this was correlated with an increase in the UGT1A1 protein concentration in hepatic microsomes. Transcriptional induction of UGT1A1 was also observed in diabetes and starvation but not with acetone treatment, which apparently caused translational stabilization of the enzyme protein. The hormonal/metabolic alterations in diabetes and starvation might be a model for postnatal development. The sudden interruption of maternal glucose supply signals the enhanced expression of UGT1A1, giving a novel explanation for the physiological induction of bilirubin glucuronidation in newborn infants.

The Impact of Renal Allograft Function on Exposure and Elimination of Mycophenolic Acid (MPA) and Its Metabolite MPA 7-O-glucuronide

“…In the current study, there was a significant univariate association between diabetes mellitus and high MPAG exposure. This could suggest that other mechanisms besides gastric emptying are playing a role, such as induction of UGT activity in diabetes mellitus, which has been observed in a diabetic rat model (49). The fact that total urinary recovery and fractional excretion of MPAG was significantly higher in patients with diabetes mellitus supports this last hypothesis.…”

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

“…Diabetes has been reported to result in increased expression of hepatic cytochromes P450 (CYP) 1A1, 2B, 3A, 4A, 2E1 and bilirubin UDP-glucuronosyltransferase (UGT1A1), whereas decreased expression of CYP2C11, microsomal epoxide hydrolase (mEH) and sulfotransferases (SULTs), such as hydroxysteroid SULT-a (SULT2A1) and aryl SULT IV (SULT1A1), has been reported, (summarized in Table 1; Bellward et al, 1988;Barnett et al, 1990;Donahue et al, 1991;Song et al, 1990;Shimojo et al, 1993;Thomas et al, 1989;RungeMorris and Vento 1995;Braun et al, 1998;Hong et al, 1987;Ronis et al, 1993;Van de Wiel et al, 1993;Kardon et al, 2000;Duvaldestin et al, 1975;Visser et al, 1996;Chaudhary et al, 1993;Abernethy et al, 1983;Woodcroft and Novak, 1997;Woodcroft and Novak, 1999a). In contrast, studies on the glutathione S-transferase (GST) gene expression and metabolic activity during diabetes report both increased and decreased GST expression or activity reported in vivo (Rouer et al, 1981;Agius and Gidari, 1985;Grant and Duthie, 1987;Thomas et al, 1989;Mukherjee et al, 1994;Raza et al, 1996).…”

Transcriptional Regulation of Human UGT1A1 Gene Expression: Activated Glucocorticoid Receptor Enhances constitutive Androstane Receptor/Pregnane X Receptor-Mediated UDP-Glucuronosyltransferase 1A1 Regulation with Glucocorticoid Receptor-Interacting Protein 1

“…Recent study suggests that a functional deficit of CAR activity in neonatal human liver may account for low levels of bilirubin UDP-glucuronosyltransferase activity, which is associated with physiological neonatal jaundice, together with an increased rate of erythrocyte turnover (Huang et al, 2003). Braun et al (1998) have reported that transcriptional induction of UGT1A1 was observed in diabetic rats and starved rats. Because the normal/metabolic alterations observed in diabetes and starvation are considered comparable with the postnatal metabolic state, Braun et al (1998) have further suggested that the sudden interruption of maternal glucose supply could signal enhanced expression of UGT1A1 in newborn infants.…”

“…Braun et al (1998) have reported that transcriptional induction of UGT1A1 was observed in diabetic rats and starved rats. Because the normal/metabolic alterations observed in diabetes and starvation are considered comparable with the postnatal metabolic state, Braun et al (1998) have further suggested that the sudden interruption of maternal glucose supply could signal enhanced expression of UGT1A1 in newborn infants. However, it was previously shown that shortterm starvation (72-h fasting) induces significant increases in the 24-h mean cortisol concentration in healthy men (Chan et al, 2003).…”