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• W2017805648 abstract "A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.Yin Zhi Huang, a decoction of Yin Chin (Artemisia capillaris) and three other herbs, is widely used in Asia to prevent and treat neonatal jaundice. We recently identified the constitutive androstane receptor (CAR, NR1I3) as a key regulator of bilirubin clearance in the liver. Here we show that treatment of WT and humanized CAR transgenic mice with Yin Zhi Huang for 3 days accelerates the clearance of intravenously infused bilirubin. This effect is absent in CAR knockout animals. Expression of bilirubin glucuronyl transferase and other components of the bilirubin metabolism pathway is induced by Yin Zhi Huang treatment of WT mice or mice expressing only human CAR, but not CAR knockout animals. 6,7-Dimethylesculetin, a compound present in Yin Chin, activates CAR in primary hepatocytes from both WT and humanized CAR mice and accelerates bilirubin clearance in vivo. We conclude that CAR mediates the effects of Yin Zhi Huang on bilirubin clearance and that 6,7-dimethylesculetin is an active component of this herbal medicine. CAR is a potential target for the development of new drugs to treat neonatal, genetic, or acquired forms of jaundice.[Abstract reproduced by permission of J Clin Invest 2004;113:137–143] A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. Yin Zhi Huang, a decoction of Yin Chin (Artemisia capillaris) and three other herbs, is widely used in Asia to prevent and treat neonatal jaundice. We recently identified the constitutive androstane receptor (CAR, NR1I3) as a key regulator of bilirubin clearance in the liver. Here we show that treatment of WT and humanized CAR transgenic mice with Yin Zhi Huang for 3 days accelerates the clearance of intravenously infused bilirubin. This effect is absent in CAR knockout animals. Expression of bilirubin glucuronyl transferase and other components of the bilirubin metabolism pathway is induced by Yin Zhi Huang treatment of WT mice or mice expressing only human CAR, but not CAR knockout animals. 6,7-Dimethylesculetin, a compound present in Yin Chin, activates CAR in primary hepatocytes from both WT and humanized CAR mice and accelerates bilirubin clearance in vivo. We conclude that CAR mediates the effects of Yin Zhi Huang on bilirubin clearance and that 6,7-dimethylesculetin is an active component of this herbal medicine. CAR is a potential target for the development of new drugs to treat neonatal, genetic, or acquired forms of jaundice. [Abstract reproduced by permission of J Clin Invest 2004;113:137–143] Our present day Western health care is supposed to be driven by evidence-based medicine. The introduction of a new drug is only allowed after intense toxicological screening and after it is shown to be more efficacious than conventional treatment on the basis of thorough scientific criteria. In contrast, herbal medicine relies on centuries of experience with treatment using crude plant extracts. These quite different approaches of a patient's ailment are often regarded as conflicting, but this is not necessarily the case. Recent studies provide molecular biological explanations for the mechanism of certain treatments in herbal medicine. This is the case of the paper by Huang et al. [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] and of other studies summarized in this commentary. This not only shows that some of these herbal preparations bear value but also provides new possibilities for drug development that meet with the requirements of evidence based medicine.In the last few years it has become clear that expression of many drug metabolizing enzymes and drug transporters is regulated by a subgroup of (former orphan) nuclear receptors which are ligand-induced transcription factors. Nuclear receptors, like the Pregnane X receptor (PXR), the Constitutive Androstane Receptor (CAR) and the Farnesoid X Receptor (FXR) turn out to tightly regulate the expression of metabolizing enzymes such as the Cytochrome P450s and glucuronyltransferases as well as transporters such as MDR1 P-glycoprotein and the MRP's. The ligands for these receptors are often the drugs that their gene products metabolize. Usually drug metabolizing enzymes as well as the drug transporters have a very broad substrate specificity and so do these nuclear receptors. Taking this into account many drug–drug interactions can potentially be explained [[2]Sonoda J. Rosenfeld J.M. Xu L. Evans R.M. Xie W. A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection.Curr Drug Metab. 2003; 4: 59-72Crossref PubMed Scopus (83) Google Scholar].1. Ying Zhi Huang, a traditional Chinese herbal medicine, and jaundiceImportantly, regulation of gene expression through nuclear receptors does not only pertain to drugs but also to valuable endogenous compounds such as bile salts or endogenous waste products such as bilirubin. As an example, bilirubin metabolism appears to be tightly regulated by the nuclear receptor CAR, which is not surprising because bilirubin is quite a toxic compound.Accumulation of bilirubin occurs very often in newborns and especially in premature babies. It is caused by neonatal immaturity of the metabolic machinery for this breakdown product of heme (‘physiological jaundice’). This form of jaundice is usually regarded as benign if the serum levels do not become too high and jaundice is transient. It is mitigated by phototherapy with blue light which induces formation of photoisomers in the skin that can be disposed of into bile. Mild genetic deficiency of the bilirubin conjugating enzyme, UDP-glucuronosyltransferase 1A1 (UGT1A1), occurs in individuals with the Gilbert syndrome who have a polymorphism in the promoter region of this gene [[3]Bosma P.J. Chowdhury J.R. Bakker C. Gantla S. de Boer A. Oostra B.A. et al.The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome [see comments].New Engl. J. Med. 1995; 333: 1171-1175Crossref PubMed Scopus (1263) Google Scholar]. Although these individuals turn out to have an enhanced sensitivity towards certain drugs like irinotecan [[4]Innocenti F. Iyer L. Ratain M.J. Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.Drug Metab Dispos. 2001; 29: 596-600PubMed Google Scholar], the syndrome is generally regarded as benign. Complete or near complete deficiency of UGT1A1 is a life threatening disorder and occurs in the rare pediatric Crigler Najjar syndrome. In these patients unconjugated bilirubin levels in plasma reach higher concentrations than albumin can bind and this leads to central neurotoxicity (kernicterus). These patients often need liver transplantation but are also treated with intense phototherapy. If residual activity of the enzyme is present (type 2 patients) this can be induced by chronic treatment with phenobarbital, but this has considerable side effects.In order to become conjugated, bilirubin is taken up into the hepatocyte (either or not via one of the organic anion transporter proteins, OATPs [[5]Wang P. Kim R.B. Chowdhury J.R. Wolkoff A.W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport.J Biol Chem. 2003; 278: 20695-20699Crossref PubMed Scopus (81) Google Scholar]). Within the cytosol, the toxic molecule is tightly bound to glutathione S-transferase A (GSTA; ligandin) and conjugated by UGT1A1 in the endoplasmic reticulum. Subsequently, conjugated bilirubin is excreted into bile via MRP2.The group of David Moore [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] has shown earlier that all these genes are regulated by the nuclear receptor CAR. Since it has been shown that phenobarbital induces CAR, it may be assumed that phenobarbital induction of residual UGT1A1 activity in Crigler Najjar patients acts via this receptor. Interestingly, bilirubin itself also induces these genes and this induction is absent in CAR knockout mice, suggesting that bilirubin, like phenobarbital, induces CAR-mediated gene expression.Yin Zhi Huang (YZH), a decoction of Yin Chin, represents a traditional Asian treatment of neonatal jaundice [[6]Fok T.F. Neonatal jaundice—traditional Chinese medicine approach.J Perinatol. 2001; 21: S98-S100Crossref PubMed Scopus (50) Google Scholar]. Indeed, in studies with rats this herbal preparation was found to induce both glucuronosyltransferase activity and ligandin [[7]Yin J. Miller M. Wennberg R.P. Induction of hepatic bilirubin-metabolizing enzymes by the traditional Chinese medicine yin zhi huang.Dev Pharmacol Ther. 1991; 16: 176-184PubMed Google Scholar]. Recently, Huang et al. [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] demonstrated that this effect could be mimicked in mice and that this induction was absent in CAR knockout mice. In addition, treatment with YZH induced Ugt1a1, Mrp2 and Gsta expression in normal mice but not in CAR knockout mice. Finally, 6,7-Dimethylesculetin, the supposed active compound in this decoction, was found to induce Mrp2 and Ugt1a1 expression in a CAR-dependent fashion. With these data a 3000 years old traditional treatment of neonatal jaundice might be explained: a modern reductionist explanation for an old holistic treatment. It might not only validate the old treatment but also provide new possibilities for drug development. Yet, uncertainties remain, which have to be solved before this can lead to translation into a modern drug. Actually, it is a bit striking that Yin Zhi Huang would work via this mechanism since Huang et al. [[8]Huang W. Zhang J. Chua S.S. Qatanani M. Han Y. Granata R. et al.Induction of bilirubin clearance by the constitutive androstane receptor (CAR).Proc Natl Acad Sci USA. 2003; 100: 4156-4161Crossref PubMed Scopus (329) Google Scholar] demonstrated that CAR expression in neonates is minimal. Hence, activation of CAR is not expected to have much effect unless it also induces its own expression. The latter possibility is not unlikely as this was recently found to occur for another nuclear receptor, FXR [[9]Lew J.L. Zhao A. Yu J. Huang L. De Pedro N. Pelaez F. et al.The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion.J Biol Chem. 2004; 279: 8856-8861Crossref PubMed Scopus (164) Google Scholar].2. Gum Guggul for hyperlipidemiaAyurveda is a holistic system of healing which evolved among the Brahmin sages of ancient India some 3000–5000 years ago [[10]Chopra A. Doiphode V.V. Ayurvedic medicine. Core concept, therapeutic principles, and current relevance.Med Clin North Am. 2002; 86: 75-89Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. Guggulu is the oleogum resin from a small tree (Commiphora mukul) that grows in Northwestern India. In Ayurvedic Medicine it is used for its anti-inflammatory and lipid-lowering actions. Urizar et al. [[11]Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. et al.A natural product that lowers cholesterol as an antagonist ligand for FXR.Science. 2002; 296: 1703-1706Crossref PubMed Scopus (425) Google Scholar], again from the Moore's group, have recently demonstrated that 4,17[20]-pregnadiene-3,16-dione (guggulsterone), an active component from the guggul extract, acts as an antagonist of the nuclear receptor FXR. FXR was recently recognized as a bile salt sensor with several key enzymes and transporters in cholesterol and bile salt homeostasis as target genes. Urizar et al. observed that guggulsterone prevents hepatic cholesterol accumulation in mice on a high cholesterol diet. Importantly, this lipid-lowering effect was absent in FXR knockout mice, suggesting that guggulsterone may lower lipid levels by inhibiting the transcriptional activity of FXR. How antagonism of FXR mechanistically relates to the lipid lowering effect is as yet unclear. At the same time guggulsterone appears to be a weak activator of the nuclear receptor PXR, which is an important regulator of many drug-metabolizing genes. Established PXR agonists do not lower lipid levels in mice fed a high-cholesterol diet excluding a role for PXR. However, the interaction with PXR may explain the observed interactions of guggulsterone with other drugs [[12]Urizar N.L. Moore D.D. Gugulipid: a natural cholesterol-lowering agent.Annu Rev Nutr. 2003; 23: 303-313Crossref PubMed Scopus (211) Google Scholar].3. St John's Wort and Kava-kava; prototypic drug interactionsOur new knowledge about the regulation of drug metabolism by nuclear receptors may help us to explain some of the side effects observed with herbal treatments. St John's Wort and kava-kava are herbal preparations that are widely used for their anti-depressive and anxiolytic action, respectively. Both herbal preparations can have considerable side effects. St John's Wort is an herb that has been used for centuries for medicinal purposes. In Europe, St John's Wort is presently widely prescribed for depression. In the United States, although not a prescribed medication, St John's Wort remains among the top-selling herbal products. One of the powerful bioactive components of St John's Wort is hyperforin [[13]Wagner H. Bladt S. Pharmaceutical quality of hypericum extracts.J Geriatr Psychiatry Neurol. 1994; 7: S65-S68Crossref PubMed Scopus (82) Google Scholar]. Hyperforin causes a 7-fold induction of transcription driven by CYP3A promoter constructs and this induction depends on the presence of PXR [[14]Moore L.B. Goodwin B. Jones S.A. Wisely G.B. Serabjit-Singh C.J. Willson T.M. et al.Proc Natl Acad Sci USA. 2000; 97: 7500-7502Crossref PubMed Scopus (858) Google Scholar]. Very similar findings were reported for the human counterpart SXR [[15]Wentworth J.M. Agostini M. Love J. Schwabe J.W. Chatterjee V.K. St John's Wort, a herbal antidepressant, activates the steroid X receptor.J Endocrinol. 2000; 166: R11-R16Crossref PubMed Scopus (223) Google Scholar]. Hyperforin not only influences drug metabolism but also drug transport as it was shown earlier that MDR1 P-glycoprotein expression is strongly induced by hyperforin and, again, this induction depends on PXR or SXR [16Synold T.W. Dussault I. Forman B.M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.Nat Med. 2001; 7: 584-590Crossref PubMed Scopus (754) Google Scholar, 17Geick A. Eichelbaum M. Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.J Biol Chem. 2001; 276: 14581-14587Crossref PubMed Scopus (757) Google Scholar]. Hence, hyperforin is a strong modulator of drug metabolism and disposition and this explains many drug interactions. As an example, the use of St John's Wort during oral treatment with Cyclosporin A causes a dramatic drop in plasma levels of the immunosuppressant [[18]Bauer S. Stormer E. Johne A. Kruger H. Budde K. Neumayer H.H. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's Wort in renal transplant patients.Br J Clin Pharmacol. 2003; 55: 203-211Crossref PubMed Scopus (163) Google Scholar]. It is difficult to assess to what extent this is caused by reduced uptake in the gut, since hyperforin not only induces expression of MDR1 but also induces expression of CYP3A4, leading to enhanced metabolism.Clearly, hyperforin is just one (potent) example of many compounds that may regulate gene expression through these drug sensitive nuclear receptors.A last example represents kava-kava; kava is the name given by Pacific islanders to Piper methysticum, a shrub belonging to the pepper family Piperaceae. Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Clinical trials suggest that kava extract might have therapeutic value for people with generalised anxiety disorder, but its use has been associated with incidents of liver damage, and in Britain it has been voluntarily withdrawn from the market [[19]Tonks A. Treating generalised anxiety disorder.BMJ. 2003; 326: 700-702Crossref PubMed Google Scholar]. It was shown recently, that kava extract may be a potent inducer of PXR signalling. In the presence of PXR it caused an 11-fold induction of transcription driven by a CYP3A4 enhancer [[20]Raucy J.L. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.Drug Metab Dispos. 2003; 31: 533-539Crossref PubMed Scopus (223) Google Scholar]. Although this by no means explains the incidental hepatotoxicity, it shows that this extract can have potent regulatory effects on gene expression with profound alterations in drug metabolism and disposition as a consequence.These examples demonstrate that the rapidly developing knowledge on ligand-induced transcription factors will help to identify drug–drug interactions; this will be of great use in the development of useful and reliable new drugs. Our present day Western health care is supposed to be driven by evidence-based medicine. The introduction of a new drug is only allowed after intense toxicological screening and after it is shown to be more efficacious than conventional treatment on the basis of thorough scientific criteria. In contrast, herbal medicine relies on centuries of experience with treatment using crude plant extracts. These quite different approaches of a patient's ailment are often regarded as conflicting, but this is not necessarily the case. Recent studies provide molecular biological explanations for the mechanism of certain treatments in herbal medicine. This is the case of the paper by Huang et al. [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] and of other studies summarized in this commentary. This not only shows that some of these herbal preparations bear value but also provides new possibilities for drug development that meet with the requirements of evidence based medicine. In the last few years it has become clear that expression of many drug metabolizing enzymes and drug transporters is regulated by a subgroup of (former orphan) nuclear receptors which are ligand-induced transcription factors. Nuclear receptors, like the Pregnane X receptor (PXR), the Constitutive Androstane Receptor (CAR) and the Farnesoid X Receptor (FXR) turn out to tightly regulate the expression of metabolizing enzymes such as the Cytochrome P450s and glucuronyltransferases as well as transporters such as MDR1 P-glycoprotein and the MRP's. The ligands for these receptors are often the drugs that their gene products metabolize. Usually drug metabolizing enzymes as well as the drug transporters have a very broad substrate specificity and so do these nuclear receptors. Taking this into account many drug–drug interactions can potentially be explained [[2]Sonoda J. Rosenfeld J.M. Xu L. Evans R.M. Xie W. A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection.Curr Drug Metab. 2003; 4: 59-72Crossref PubMed Scopus (83) Google Scholar]. 1. Ying Zhi Huang, a traditional Chinese herbal medicine, and jaundiceImportantly, regulation of gene expression through nuclear receptors does not only pertain to drugs but also to valuable endogenous compounds such as bile salts or endogenous waste products such as bilirubin. As an example, bilirubin metabolism appears to be tightly regulated by the nuclear receptor CAR, which is not surprising because bilirubin is quite a toxic compound.Accumulation of bilirubin occurs very often in newborns and especially in premature babies. It is caused by neonatal immaturity of the metabolic machinery for this breakdown product of heme (‘physiological jaundice’). This form of jaundice is usually regarded as benign if the serum levels do not become too high and jaundice is transient. It is mitigated by phototherapy with blue light which induces formation of photoisomers in the skin that can be disposed of into bile. Mild genetic deficiency of the bilirubin conjugating enzyme, UDP-glucuronosyltransferase 1A1 (UGT1A1), occurs in individuals with the Gilbert syndrome who have a polymorphism in the promoter region of this gene [[3]Bosma P.J. Chowdhury J.R. Bakker C. Gantla S. de Boer A. Oostra B.A. et al.The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome [see comments].New Engl. J. Med. 1995; 333: 1171-1175Crossref PubMed Scopus (1263) Google Scholar]. Although these individuals turn out to have an enhanced sensitivity towards certain drugs like irinotecan [[4]Innocenti F. Iyer L. Ratain M.J. Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.Drug Metab Dispos. 2001; 29: 596-600PubMed Google Scholar], the syndrome is generally regarded as benign. Complete or near complete deficiency of UGT1A1 is a life threatening disorder and occurs in the rare pediatric Crigler Najjar syndrome. In these patients unconjugated bilirubin levels in plasma reach higher concentrations than albumin can bind and this leads to central neurotoxicity (kernicterus). These patients often need liver transplantation but are also treated with intense phototherapy. If residual activity of the enzyme is present (type 2 patients) this can be induced by chronic treatment with phenobarbital, but this has considerable side effects.In order to become conjugated, bilirubin is taken up into the hepatocyte (either or not via one of the organic anion transporter proteins, OATPs [[5]Wang P. Kim R.B. Chowdhury J.R. Wolkoff A.W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport.J Biol Chem. 2003; 278: 20695-20699Crossref PubMed Scopus (81) Google Scholar]). Within the cytosol, the toxic molecule is tightly bound to glutathione S-transferase A (GSTA; ligandin) and conjugated by UGT1A1 in the endoplasmic reticulum. Subsequently, conjugated bilirubin is excreted into bile via MRP2.The group of David Moore [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] has shown earlier that all these genes are regulated by the nuclear receptor CAR. Since it has been shown that phenobarbital induces CAR, it may be assumed that phenobarbital induction of residual UGT1A1 activity in Crigler Najjar patients acts via this receptor. Interestingly, bilirubin itself also induces these genes and this induction is absent in CAR knockout mice, suggesting that bilirubin, like phenobarbital, induces CAR-mediated gene expression.Yin Zhi Huang (YZH), a decoction of Yin Chin, represents a traditional Asian treatment of neonatal jaundice [[6]Fok T.F. Neonatal jaundice—traditional Chinese medicine approach.J Perinatol. 2001; 21: S98-S100Crossref PubMed Scopus (50) Google Scholar]. Indeed, in studies with rats this herbal preparation was found to induce both glucuronosyltransferase activity and ligandin [[7]Yin J. Miller M. Wennberg R.P. Induction of hepatic bilirubin-metabolizing enzymes by the traditional Chinese medicine yin zhi huang.Dev Pharmacol Ther. 1991; 16: 176-184PubMed Google Scholar]. Recently, Huang et al. [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] demonstrated that this effect could be mimicked in mice and that this induction was absent in CAR knockout mice. In addition, treatment with YZH induced Ugt1a1, Mrp2 and Gsta expression in normal mice but not in CAR knockout mice. Finally, 6,7-Dimethylesculetin, the supposed active compound in this decoction, was found to induce Mrp2 and Ugt1a1 expression in a CAR-dependent fashion. With these data a 3000 years old traditional treatment of neonatal jaundice might be explained: a modern reductionist explanation for an old holistic treatment. It might not only validate the old treatment but also provide new possibilities for drug development. Yet, uncertainties remain, which have to be solved before this can lead to translation into a modern drug. Actually, it is a bit striking that Yin Zhi Huang would work via this mechanism since Huang et al. [[8]Huang W. Zhang J. Chua S.S. Qatanani M. Han Y. Granata R. et al.Induction of bilirubin clearance by the constitutive androstane receptor (CAR).Proc Natl Acad Sci USA. 2003; 100: 4156-4161Crossref PubMed Scopus (329) Google Scholar] demonstrated that CAR expression in neonates is minimal. Hence, activation of CAR is not expected to have much effect unless it also induces its own expression. The latter possibility is not unlikely as this was recently found to occur for another nuclear receptor, FXR [[9]Lew J.L. Zhao A. Yu J. Huang L. De Pedro N. Pelaez F. et al.The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion.J Biol Chem. 2004; 279: 8856-8861Crossref PubMed Scopus (164) Google Scholar]. Importantly, regulation of gene expression through nuclear receptors does not only pertain to drugs but also to valuable endogenous compounds such as bile salts or endogenous waste products such as bilirubin. As an example, bilirubin metabolism appears to be tightly regulated by the nuclear receptor CAR, which is not surprising because bilirubin is quite a toxic compound. Accumulation of bilirubin occurs very often in newborns and especially in premature babies. It is caused by neonatal immaturity of the metabolic machinery for this breakdown product of heme (‘physiological jaundice’). This form of jaundice is usually regarded as benign if the serum levels do not become too high and jaundice is transient. It is mitigated by phototherapy with blue light which induces formation of photoisomers in the skin that can be disposed of into bile. Mild genetic deficiency of the bilirubin conjugating enzyme, UDP-glucuronosyltransferase 1A1 (UGT1A1), occurs in individuals with the Gilbert syndrome who have a polymorphism in the promoter region of this gene [[3]Bosma P.J. Chowdhury J.R. Bakker C. Gantla S. de Boer A. Oostra B.A. et al.The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome [see comments].New Engl. J. Med. 1995; 333: 1171-1175Crossref PubMed Scopus (1263) Google Scholar]. Although these individuals turn out to have an enhanced sensitivity towards certain drugs like irinotecan [[4]Innocenti F. Iyer L. Ratain M.J. Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.Drug Metab Dispos. 2001; 29: 596-600PubMed Google Scholar], the syndrome is generally regarded as benign. Complete or near complete deficiency of UGT1A1 is a life threatening disorder and occurs in the rare pediatric Crigler Najjar syndrome. In these patients unconjugated bilirubin levels in plasma reach higher concentrations than albumin can bind and this leads to central neurotoxicity (kernicterus). These patients often need liver transplantation but are also treated with intense phototherapy. If residual activity of the enzyme is present (type 2 patients) this can be induced by chronic treatment with phenobarbital, but this has considerable side effects. In order to become conjugated, bilirubin is taken up into the hepatocyte (either or not via one of the organic anion transporter proteins, OATPs [[5]Wang P. Kim R.B. Chowdhury J.R. Wolkoff A.W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport.J Biol Chem. 2003; 278: 20695-20699Crossref PubMed Scopus (81) Google Scholar]). Within the cytosol, the toxic molecule is tightly bound to glutathione S-transferase A (GSTA; ligandin) and conjugated by UGT1A1 in the endoplasmic reticulum. Subsequently, conjugated bilirubin is excreted into bile via MRP2. The group of David Moore [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] has shown earlier that all these genes are regulated by the nuclear receptor CAR. Since it has been shown that phenobarbital induces CAR, it may be assumed that phenobarbital induction of residual UGT1A1 activity in Crigler Najjar patients acts via this receptor. Interestingly, bilirubin itself also induces these genes and this induction is absent in CAR knockout mice, suggesting that bilirubin, like phenobarbital, induces CAR-mediated gene expression. Yin Zhi Huang (YZH), a decoction of Yin Chin, represents a traditional Asian treatment of neonatal jaundice [[6]Fok T.F. Neonatal jaundice—traditional Chinese medicine approach.J Perinatol. 2001; 21: S98-S100Crossref PubMed Scopus (50) Google Scholar]. Indeed, in studies with rats this herbal preparation was found to induce both glucuronosyltransferase activity and ligandin [[7]Yin J. Miller M. Wennberg R.P. Induction of hepatic bilirubin-metabolizing enzymes by the traditional Chinese medicine yin zhi huang.Dev Pharmacol Ther. 1991; 16: 176-184PubMed Google Scholar]. Recently, Huang et al. [[1]Huang W. Zhang J. Moore D.D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR.J Clin Invest. 2004; 113: 137-143Crossref PubMed Scopus (206) Google Scholar] demonstrated that this effect could be mimicked in mice and that this induction was absent in CAR knockout mice. In addition, treatment with YZH induced Ugt1a1, Mrp2 and Gsta expression in normal mice but not in CAR knockout mice. Finally, 6,7-Dimethylesculetin, the supposed active compound in this decoction, was found to induce Mrp2 and Ugt1a1 expression in a CAR-dependent fashion. With these data a 3000 years old traditional treatment of neonatal jaundice might be explained: a modern reductionist explanation for an old holistic treatment. It might not only validate the old treatment but also provide new possibilities for drug development. Yet, uncertainties remain, which have to be solved before this can lead to translation into a modern drug. Actually, it is a bit striking that Yin Zhi Huang would work via this mechanism since Huang et al. [[8]Huang W. Zhang J. Chua S.S. Qatanani M. Han Y. Granata R. et al.Induction of bilirubin clearance by the constitutive androstane receptor (CAR).Proc Natl Acad Sci USA. 2003; 100: 4156-4161Crossref PubMed Scopus (329) Google Scholar] demonstrated that CAR expression in neonates is minimal. Hence, activation of CAR is not expected to have much effect unless it also induces its own expression. The latter possibility is not unlikely as this was recently found to occur for another nuclear receptor, FXR [[9]Lew J.L. Zhao A. Yu J. Huang L. De Pedro N. Pelaez F. et al.The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion.J Biol Chem. 2004; 279: 8856-8861Crossref PubMed Scopus (164) Google Scholar]. 2. Gum Guggul for hyperlipidemiaAyurveda is a holistic system of healing which evolved among the Brahmin sages of ancient India some 3000–5000 years ago [[10]Chopra A. Doiphode V.V. Ayurvedic medicine. Core concept, therapeutic principles, and current relevance.Med Clin North Am. 2002; 86: 75-89Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. Guggulu is the oleogum resin from a small tree (Commiphora mukul) that grows in Northwestern India. In Ayurvedic Medicine it is used for its anti-inflammatory and lipid-lowering actions. Urizar et al. [[11]Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. et al.A natural product that lowers cholesterol as an antagonist ligand for FXR.Science. 2002; 296: 1703-1706Crossref PubMed Scopus (425) Google Scholar], again from the Moore's group, have recently demonstrated that 4,17[20]-pregnadiene-3,16-dione (guggulsterone), an active component from the guggul extract, acts as an antagonist of the nuclear receptor FXR. FXR was recently recognized as a bile salt sensor with several key enzymes and transporters in cholesterol and bile salt homeostasis as target genes. Urizar et al. observed that guggulsterone prevents hepatic cholesterol accumulation in mice on a high cholesterol diet. Importantly, this lipid-lowering effect was absent in FXR knockout mice, suggesting that guggulsterone may lower lipid levels by inhibiting the transcriptional activity of FXR. How antagonism of FXR mechanistically relates to the lipid lowering effect is as yet unclear. At the same time guggulsterone appears to be a weak activator of the nuclear receptor PXR, which is an important regulator of many drug-metabolizing genes. Established PXR agonists do not lower lipid levels in mice fed a high-cholesterol diet excluding a role for PXR. However, the interaction with PXR may explain the observed interactions of guggulsterone with other drugs [[12]Urizar N.L. Moore D.D. Gugulipid: a natural cholesterol-lowering agent.Annu Rev Nutr. 2003; 23: 303-313Crossref PubMed Scopus (211) Google Scholar]. Ayurveda is a holistic system of healing which evolved among the Brahmin sages of ancient India some 3000–5000 years ago [[10]Chopra A. Doiphode V.V. Ayurvedic medicine. Core concept, therapeutic principles, and current relevance.Med Clin North Am. 2002; 86: 75-89Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. Guggulu is the oleogum resin from a small tree (Commiphora mukul) that grows in Northwestern India. In Ayurvedic Medicine it is used for its anti-inflammatory and lipid-lowering actions. Urizar et al. [[11]Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. et al.A natural product that lowers cholesterol as an antagonist ligand for FXR.Science. 2002; 296: 1703-1706Crossref PubMed Scopus (425) Google Scholar], again from the Moore's group, have recently demonstrated that 4,17[20]-pregnadiene-3,16-dione (guggulsterone), an active component from the guggul extract, acts as an antagonist of the nuclear receptor FXR. FXR was recently recognized as a bile salt sensor with several key enzymes and transporters in cholesterol and bile salt homeostasis as target genes. Urizar et al. observed that guggulsterone prevents hepatic cholesterol accumulation in mice on a high cholesterol diet. Importantly, this lipid-lowering effect was absent in FXR knockout mice, suggesting that guggulsterone may lower lipid levels by inhibiting the transcriptional activity of FXR. How antagonism of FXR mechanistically relates to the lipid lowering effect is as yet unclear. At the same time guggulsterone appears to be a weak activator of the nuclear receptor PXR, which is an important regulator of many drug-metabolizing genes. Established PXR agonists do not lower lipid levels in mice fed a high-cholesterol diet excluding a role for PXR. However, the interaction with PXR may explain the observed interactions of guggulsterone with other drugs [[12]Urizar N.L. Moore D.D. Gugulipid: a natural cholesterol-lowering agent.Annu Rev Nutr. 2003; 23: 303-313Crossref PubMed Scopus (211) Google Scholar]. 3. St John's Wort and Kava-kava; prototypic drug interactionsOur new knowledge about the regulation of drug metabolism by nuclear receptors may help us to explain some of the side effects observed with herbal treatments. St John's Wort and kava-kava are herbal preparations that are widely used for their anti-depressive and anxiolytic action, respectively. Both herbal preparations can have considerable side effects. St John's Wort is an herb that has been used for centuries for medicinal purposes. In Europe, St John's Wort is presently widely prescribed for depression. In the United States, although not a prescribed medication, St John's Wort remains among the top-selling herbal products. One of the powerful bioactive components of St John's Wort is hyperforin [[13]Wagner H. Bladt S. Pharmaceutical quality of hypericum extracts.J Geriatr Psychiatry Neurol. 1994; 7: S65-S68Crossref PubMed Scopus (82) Google Scholar]. Hyperforin causes a 7-fold induction of transcription driven by CYP3A promoter constructs and this induction depends on the presence of PXR [[14]Moore L.B. Goodwin B. Jones S.A. Wisely G.B. Serabjit-Singh C.J. Willson T.M. et al.Proc Natl Acad Sci USA. 2000; 97: 7500-7502Crossref PubMed Scopus (858) Google Scholar]. Very similar findings were reported for the human counterpart SXR [[15]Wentworth J.M. Agostini M. Love J. Schwabe J.W. Chatterjee V.K. St John's Wort, a herbal antidepressant, activates the steroid X receptor.J Endocrinol. 2000; 166: R11-R16Crossref PubMed Scopus (223) Google Scholar]. Hyperforin not only influences drug metabolism but also drug transport as it was shown earlier that MDR1 P-glycoprotein expression is strongly induced by hyperforin and, again, this induction depends on PXR or SXR [16Synold T.W. Dussault I. Forman B.M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.Nat Med. 2001; 7: 584-590Crossref PubMed Scopus (754) Google Scholar, 17Geick A. Eichelbaum M. Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.J Biol Chem. 2001; 276: 14581-14587Crossref PubMed Scopus (757) Google Scholar]. Hence, hyperforin is a strong modulator of drug metabolism and disposition and this explains many drug interactions. As an example, the use of St John's Wort during oral treatment with Cyclosporin A causes a dramatic drop in plasma levels of the immunosuppressant [[18]Bauer S. Stormer E. Johne A. Kruger H. Budde K. Neumayer H.H. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's Wort in renal transplant patients.Br J Clin Pharmacol. 2003; 55: 203-211Crossref PubMed Scopus (163) Google Scholar]. It is difficult to assess to what extent this is caused by reduced uptake in the gut, since hyperforin not only induces expression of MDR1 but also induces expression of CYP3A4, leading to enhanced metabolism.Clearly, hyperforin is just one (potent) example of many compounds that may regulate gene expression through these drug sensitive nuclear receptors.A last example represents kava-kava; kava is the name given by Pacific islanders to Piper methysticum, a shrub belonging to the pepper family Piperaceae. Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Clinical trials suggest that kava extract might have therapeutic value for people with generalised anxiety disorder, but its use has been associated with incidents of liver damage, and in Britain it has been voluntarily withdrawn from the market [[19]Tonks A. Treating generalised anxiety disorder.BMJ. 2003; 326: 700-702Crossref PubMed Google Scholar]. It was shown recently, that kava extract may be a potent inducer of PXR signalling. In the presence of PXR it caused an 11-fold induction of transcription driven by a CYP3A4 enhancer [[20]Raucy J.L. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.Drug Metab Dispos. 2003; 31: 533-539Crossref PubMed Scopus (223) Google Scholar]. Although this by no means explains the incidental hepatotoxicity, it shows that this extract can have potent regulatory effects on gene expression with profound alterations in drug metabolism and disposition as a consequence.These examples demonstrate that the rapidly developing knowledge on ligand-induced transcription factors will help to identify drug–drug interactions; this will be of great use in the development of useful and reliable new drugs. Our new knowledge about the regulation of drug metabolism by nuclear receptors may help us to explain some of the side effects observed with herbal treatments. St John's Wort and kava-kava are herbal preparations that are widely used for their anti-depressive and anxiolytic action, respectively. Both herbal preparations can have considerable side effects. St John's Wort is an herb that has been used for centuries for medicinal purposes. In Europe, St John's Wort is presently widely prescribed for depression. In the United States, although not a prescribed medication, St John's Wort remains among the top-selling herbal products. One of the powerful bioactive components of St John's Wort is hyperforin [[13]Wagner H. Bladt S. Pharmaceutical quality of hypericum extracts.J Geriatr Psychiatry Neurol. 1994; 7: S65-S68Crossref PubMed Scopus (82) Google Scholar]. Hyperforin causes a 7-fold induction of transcription driven by CYP3A promoter constructs and this induction depends on the presence of PXR [[14]Moore L.B. Goodwin B. Jones S.A. Wisely G.B. Serabjit-Singh C.J. Willson T.M. et al.Proc Natl Acad Sci USA. 2000; 97: 7500-7502Crossref PubMed Scopus (858) Google Scholar]. Very similar findings were reported for the human counterpart SXR [[15]Wentworth J.M. Agostini M. Love J. Schwabe J.W. Chatterjee V.K. St John's Wort, a herbal antidepressant, activates the steroid X receptor.J Endocrinol. 2000; 166: R11-R16Crossref PubMed Scopus (223) Google Scholar]. Hyperforin not only influences drug metabolism but also drug transport as it was shown earlier that MDR1 P-glycoprotein expression is strongly induced by hyperforin and, again, this induction depends on PXR or SXR [16Synold T.W. Dussault I. Forman B.M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.Nat Med. 2001; 7: 584-590Crossref PubMed Scopus (754) Google Scholar, 17Geick A. Eichelbaum M. Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.J Biol Chem. 2001; 276: 14581-14587Crossref PubMed Scopus (757) Google Scholar]. Hence, hyperforin is a strong modulator of drug metabolism and disposition and this explains many drug interactions. As an example, the use of St John's Wort during oral treatment with Cyclosporin A causes a dramatic drop in plasma levels of the immunosuppressant [[18]Bauer S. Stormer E. Johne A. Kruger H. Budde K. Neumayer H.H. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's Wort in renal transplant patients.Br J Clin Pharmacol. 2003; 55: 203-211Crossref PubMed Scopus (163) Google Scholar]. It is difficult to assess to what extent this is caused by reduced uptake in the gut, since hyperforin not only induces expression of MDR1 but also induces expression of CYP3A4, leading to enhanced metabolism. Clearly, hyperforin is just one (potent) example of many compounds that may regulate gene expression through these drug sensitive nuclear receptors. A last example represents kava-kava; kava is the name given by Pacific islanders to Piper methysticum, a shrub belonging to the pepper family Piperaceae. Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Clinical trials suggest that kava extract might have therapeutic value for people with generalised anxiety disorder, but its use has been associated with incidents of liver damage, and in Britain it has been voluntarily withdrawn from the market [[19]Tonks A. Treating generalised anxiety disorder.BMJ. 2003; 326: 700-702Crossref PubMed Google Scholar]. It was shown recently, that kava extract may be a potent inducer of PXR signalling. In the presence of PXR it caused an 11-fold induction of transcription driven by a CYP3A4 enhancer [[20]Raucy J.L. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.Drug Metab Dispos. 2003; 31: 533-539Crossref PubMed Scopus (223) Google Scholar]. Although this by no means explains the incidental hepatotoxicity, it shows that this extract can have potent regulatory effects on gene expression with profound alterations in drug metabolism and disposition as a consequence. These examples demonstrate that the rapidly developing knowledge on ligand-induced transcription factors will help to identify drug–drug interactions; this will be of great use in the development of useful and reliable new drugs." @default.
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• W2017805648 title "Yin Zhi Huang and other plant-derived preparations: where herbal and molecular medicine meet" @default.
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