Bilirubin, the product of heme catabolism, represents an important endobiotic of the endo-and xenobiotic metabolism system including drug-metabolizing enzymes, drug transporters, and drug-inducible ligand-activated transcription factors (LATFs). Bilirubin is of clinical concern since severe neonatal jaundice may lead to “kernicterus” and neurotoxicity (Kapitulnik, 2004). Hyperbilirubinemia in the newborn is particularly a problem in preterm infants owing to more profound hemolysis, and immaturity of liver function. However, bilirubin is also an interesting antioxidant which may attenuate atherosclerosis (Lin et al., 2008). Hence, bilirubin synthesis and its catabolism has to be strictly controlled. The key to bilirubin's elimination is glucuronidation by UDP-glucuronosyltransferase UGT1A1. However, alternative pathways of bilirubin catabolism have also been observed. For example, the dioxin TCDD, a “classical” ligand of the Ah receptor (AhR) stimulates bilirubin elimination in congenitally jaundiced, UGT1A1-defective Gunn rats (Kapitulnik and Ostrow, 1977). Furthermore, bilirubin itself activates the AhR postnatally, leading to increased transcription of CYP1A1 and CYP1A2 in Gunn rats (Kapitulnik and Gonzalez, 1993). Bilirubin and its extrahepatically formed glucuronides are taken up from blood into hepatocytes by OATP1B1 and OATP1B3 (Nies et al., 2008). Following conjugation bilirubin glucuronides are biliary secreted by ABCC2.
UGT1A1 and all the above transporters are transcriptionally regulated by the constitutive androstane receptor CAR (Huang et al., 2003). In CAR-defective mice phenobarbital-mediated induction of these proteins is absent. When human CAR is transfected into CAR-null mice phenobarbital and bilirubin itself activate CAR, the latter finding suggesting homeostatic control between enzyme substrate and activation of its major transcription factor. Bilirubin is a ligand of the AhR, a multifunctional transcription factor which induces a different set of genes than CAR in the drug metabolism system (Nguyen and Bradfield, 2008). It was discovered by the induction of aryl hydrocarbon metabolism and as mediator of dioxin toxicity. However, the AhR is also involved in development, cell proliferation, differentiation, and immune biology. The importance of the AhR in UGT1A1 induction has been demonstrated in human hepatocyte cultures treated with 3-methylcholanthrene (Ritter et al., 1999). Notably, phenobarbital and bilirubin are not ligands of CAR but activate CAR via phosphorylation/dephosphorylation pathways (Timsit and Negishi, 2007). Binding sites for CAR and the AhR have been identified in a 290-bp cluster of the human UGT1A1, termed gtPBREM (phenobarbital responsive enhancer module; Figure 1; Sugatani et al., 2005). The gtPBREM cluster contains binding sites for a number of ligand-activated transcription factors including pregnane X receptor (PXR), glucocorticoid receptors GR1 and GR2, CAR, antioxidant-responsive Nrf2 (Yueh and Tukey, 2007), AhR, and fibrate-inducible peroxisome proliferator-activated receptor PPARα (Seneko-Effenberger et al., 2007). It is important to note that the CAR binding site (gtNR1) plays a central role in UGT1A1 induction by both CAR and PXR, which is supported by site-directed mutagenesis and electrophoretic mobility shift assays (Sugatani et al., 2005). The cluster appears to be evolutionary conserved since the same arrangement of LATF-binding sites was found in the baboon (Caspersen et al., 2007). Allelic variants involved in bilirubin clearance have also been detected in the gtPBREM cluster. For example, the (TA)7 promoter polymorphism UGT1A1 *28, responsible for Gilbert's syndrome, is often in linkage disequilibrium with the T3279G polymorphism in the gtPBREM cluster (Sugatani et al., 2008).
Figure 1
Perinatal UGT1A1 Induction
It is tempting to speculate that the gtPBREM cluster of UGT1A1 is related to perinatal UGT1A1 induction and bilirubin homeostasis in the adult (Bock and Köhle, 2010; Bock, 2011). In perinatal stressful conditions glucocorticoids may be involved in UGT1A1 induction by CAR and PXR (Pascussi et al., 2008). In addition to CAR (Huang et al., 2003), activated PXR has also been demonstrated to induce UGT1A1 and enhance bilirubin clearance (Xie et al., 2003). With regard to AhR-mediated induction evidence was obtained that both AhR and Nrf2 are required for UGT induction (Yeager et al., 2009). Interestingly, CAR was found to be low in neonatal livers. Hence, the deficit of CAR activity may contribute to neonatal jaundice (Huang et al., 2003).
Bilirubin's Antioxidant Function
Ligand-activated transcription factors which bind in the distal gtPBREM cluster are operating in concert with other transcription factors such as HNF1 and HNF4 and with multiple factors of the proximal promoter. This is demonstrated by the (TA)7 and T3279G polymorphisms which synergistically reduce CAR- and AhR-mediated UGT1A1 induction not only in transfected cells (Sugatani et al., 2008) but also in human liver samples (Li et al., 2009). Decreased UGT1A1 expression leads to increased serum bilirubin which may contribute to bilirubin's antioxidant function (Stocker et al., 1987a). Albumin-bound bilirubin or conjugated bilirubin have also been shown to exhibit antioxidant activity (Stocker et al., 1987b; Wu et al., 1996; Kapitulnik and Maines, 2009). Evidence was obtained that heme oxygenase/biliverdin reductase activity and biliverdin–bilirubin redox cycles are essential for bilirubin's antioxidant and local atheroprotective functions (Baranano et al., 2002). The antioxidant action of bilirubin for lipids can be complementary to glutathione (Sedlak et al., 2009). Bilirubin may be particularly effective in reducing lipid peroxides as it easily enters the lipid environment (Zucker et al., 1999). However, bilirubin catabolism by hepatic UGT1A1 activity is also decisive for bilirubin's antioxidant function, as evidenced by many epidemiologic studies with UGT1A1 *28 homozygotes (Lin et al., 2008; Bock and Köhle, 2010, for references). Notably, UGT1A1-regulating LATFs may be therapeutic targets (Kapitulnik and Maines, 2009; Navarro et al., 2009). In conclusion, bilirubin has both neurotoxic and antioxidant functions which are keeping clinicians and basic scientists busy.
Statements
Acknowledgments
I apologize for often citing reviews instead of original papers.
References
1
BarananoD. E.RaoM.FerrisC. D.SnyderS. H. (2002). Biliverdin reductase: a major physiologic cytoprotectant. Proc. Natl. Acad. Sci. U.S.A.99, 16093–16098.10.1073/pnas.252626999
2
BockK. W. (2011). From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk. Biochem. Pharmacol.82, 9–16.10.1016/j.bcp.2011.03.011
3
BockK. W.KöhleC. (2010). Contributions of the Ah receptor to bilirubin homeostasis and its antioxidative and atheroprotective functions. Biol. Chem.391, 645–653.10.1515/BC.2010.065
4
CaspersenC. S.ReznikB.WeldyP. L.AbildskovK. M.StarkR. I.GarlandM. (2007). Molecular cloning of the baboon UDP-glucuronosyltransferase 1A gene family. Evolution of the primate UGT1 locus and relevance for models of human drug metabolism. Pharmacogenet. Genomics17, 11–24.10.1097/01.fpc.0000236323.96056.d8
5
HuangW.ZhangJ.ChuaS. S.QuatananiM.HanY.GranataR.MooreD. D. (2003). Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc. Natl. Acad. Sci. U.S.A.100, 4156–4161.10.1073/pnas.0630614100
6
KapitulnikJ. (2004). Bilirubin: an endogenous product of heme degradation with both cytotoxic and cytoprotective properties. Mol. Pharmacol.66, 773–779.10.1124/mol.104.002832
7
KapitulnikJ.GonzalezF. J. (1993). Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat. Mol. Pharmacol.43, 722–725.
8
KapitulnikJ.MainesM. D. (2009). Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin. Trends Pharmacol. Sci.30, 129–137.10.1016/j.tips.2008.12.003
9
KapitulnikJ.OstrowJ. D. (1977). Stimulation of bilirubin catabolism in jaundiced Gunn rats by an inducer of microsomal mixed-function monooxygenases. Proc. Natl. Acad. Sci. U.S.A.75, 682–685.10.1073/pnas.75.2.682
10
LiY.BuckleyD.WangS.KlaassenC. D.ZhongX. B. (2009). Genetic polymorphisms in the TATA box and upstream phenobarbital-responsive enhancer module of the UGT1A1 promoter have combined effects on UDP-glucuronosyltransferase 1A1 transcription mediated by constitutive androstane receptor, pregnane X receptor, or glucocorticoid receptor in human liver. Drug Metab. Dispos.37, 1978–1986.10.1124/dmd.108.026005
11
LinJ. P.O'DonnellC. J.SchwaigerJ. P.CupplesL. A.LingenhelA.HuntS. C.YangS.KronenbergF. (2008). Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation114, 1476–1481.10.1161/CIRCULATIONAHA.106.633206
12
NavarroS. L.PetersonS.ChenC.MakarK. W.SchwarzY.KingI. B.LiS. S.LiL.KestinM.LampeJ. W. (2009). Cruciferous vegetables feeding alters UGT1A1 activity: diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial. Cancer Prev. Res. (Phila.)2, 345–352.10.1158/1940-6207.CAPR-08-0178
13
NguyenL. P.BradfieldC. A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol.21, 102–116.10.1021/tx7001965
14
NiesA. T.SchwabM.KepplerD. (2008). Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin. Drug Metab. Toxicol.4, 545–568.10.1517/17425255.4.5.545
15
PascussiJ. M.Gerbal-ChaloinS.DuretC.Daujat-ChavanieuM.VilaremM. J.MaurelP. (2008). The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu. Rev. Pharmacol. Toxicol.48, 1–32.10.1146/annurev.pharmtox.47.120505.105349
16
RitterJ. K.KesslerF. K.ThompsonM. T.GroveA. D.AuyeungD. J.FisherR. A. (1999). Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences. Hepatology30, 476–484.10.1002/hep.510300205
17
SedlakT. W.SalehM.HigginsonD. S.PaulB. D.JuluriK. R.SnyderS. H. (2009). Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc. Natl. Acad. Sci. U.S.A.106, 5171–5176.10.1073/pnas.0813132106
18
Seneko-EffenbergerK.ChenS.Brace-SimokrakE.BonzoJ. A.YuehM. F.ArgikarU.KaedingJ.TrottierJ.RemmelR. P.RitterJ. K.BarbierO.TukeyR. H. (2007). Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor α activation. Drug Metab. Dispos.35, 419–427.10.1124/dmd.106.013243
19
StockerR.YamamotoY.McDonaghA. F.GlazerA. N.AmesB. N. (1987a). Bilirubin is an antioxidant of possible physiological importance. Science 235. 1043–1046.
20
StockerR.GlazerA. N.AmesB. N. (1987b). Antioxidant activity of albumin-bound bilirubin. Proc. Natl. Acad. Sci. U.S.A.84, 5918–5922.10.1073/pnas.84.16.5918
21
SugataniJ.MizushimaK.KakizakiS.TagakiH.MoriM.IkariA.MivaM. (2008). Transcriptional regulation of human UGT1A1 expression through distal and proximal promoter motifs: implications of defects of the UGT1A1 gene promoter. Naunyn Schmiedebergs Arch. Pharmacol.377, 597–605.10.1007/s00210-007-0226-y
22
SugataniJ.SueyoshiT.NegishiM.MivaM. (2005). Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnane X receptor and glucocorticoid receptor. Meth. Enzymol.400, 92–104.10.1016/S0076-6879(05)00006-6
23
TimsitY. E.NegishiM. (2007). CAR and PXR: the xenobiotic-sensing receptors. Steroids72, 231–246.10.1016/j.steroids.2006.12.006
24
WuT. W.FungK. P.WuJ.YangC. C.WeiselR. D. (1996). Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem. Pharmacol.51, 859–862.10.1016/0006-2952(95)02182-5
25
XieW.YeuhM. F.Radominska-PandyaA.SainiS. P. S.NegishiY.BottroffB. S.CabreraG. Y.TukeyR. H.EvansR. M. (2003). Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc. Natl. Acad. Sci. U.S.A.100, 4150–4155.10.1073/pnas.0438010100
26
YeagerR. L.ReismanS. A.AleksunesL. M.KlaassenC. D. (2009). Introducing the “TCDD-inducible AhR-Nrf2 gene battery.”Toxicol. Sci.111, 238–246.10.1093/toxsci/kfp115
27
YuehM. F.TukeyR. H. (2007). Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and transgenic UGT1 mice. J. Biol. Chem.282, 8749–8758.10.1074/jbc.M610790200
28
ZuckerS. D.GoesslingW.HoppinA. G. (1999). Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes. J. Biol. Chem.274, 10852–10862.10.1074/jbc.274.16.10852
Summary
Keywords
Ah receptor, antioxidant function, bilirubin homeostasis, CAR, Glucocorticoid receptor, Neurotoxicity, Nrf-2, UDP-glucuronosyltransferase
Citation
Bock KW (2011) Regulation of Bilirubin Clearance by Ligand-Activated Transcription Factors of the Endo- and Xenobiotic Metabolism System. Front. Pharmacol. 2:82. doi: 10.3389/fphar.2011.00082
Received
20 October 2011
Accepted
06 December 2011
Published
26 December 2011
Volume
2 - 2011
Copyright
© 2011 Bock.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: bock@uni-tuebingen.de
This article was submitted to Frontiers in Drug Metabolism and Transport, a specialty of Frontiers in Pharmacology.
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.