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1 MINI REVIEW ARTICLE published: 08 March 2012 doi: 10.3389/fphar.2012.00039 Bile pigments in pulmonary and vascular disease Stefan W. Ryter 1,2 * 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA 2 Adjunct Scientist, Lovelace Respiratory Research Institute, Albuquerque, NM, USA Edited by: The bile pigments, biliverdin, and bilirubin, are endogenously derived substances gener- Mahin D. Maines, University of ated during enzymatic heme degradation. These compounds have been shown to act as Rochester School of Medicine, USA chemical antioxidants in vitro. Bilirubin formed in tissues circulates in the serum, prior to Reviewed by: William Durante, University of undergoing hepatic conjugation and biliary excretion. The excess production of bilirubin Missouri, USA has been associated with neurotoxicity, in particular to the newborn. Nevertheless, clinical Leo Otterbein, Harvard Medical evidence suggests that mild states of hyperbilirubinemia may be benecial in protect- School, USA ing against cardiovascular disease in adults. Pharmacological application of either bilirubin *Correspondence: and/or its biological precursor biliverdin, can provide therapeutic benet in several animal Stefan W. Ryter , Division of Pulmonary and Critical Care Medicine, models of cardiovascular and pulmonary disease. Furthermore, biliverdin and bilirubin can Department of Medicine, Brigham confer protection against ischemia/reperfusion injury and graft rejection secondary to organ and Womens Hospital, 75 Francis transplantation in animal models. Several possible mechanisms for these effects have been Street, Boston, MA 02115, USA. proposed, including direct antioxidant and scavenging effects, and modulation of signaling e-mail: [email protected] pathways regulating inammation, apoptosis, cell proliferation, and immune responses.The practicality and therapeutic-effectiveness of bile pigment application to humans remains unclear. Keywords: antioxidant, biliverdin, bilirubin, cardiovascular disease, pulmonary disease INTRODUCTION including organ transplantation, lung disease, and CVD (Ollinger Natural antioxidants constitute an important part of host defenses et al., 2007; Ryter et al., 2007). These effects involve antioxidant, against environmental exposure to noxious agents (Davies, 1995). anti-inammatory, anti-apoptotic, and anti-proliferative mech- Pro-oxidant states arise when reactive oxygen species (ROS) anisms (Ollinger et al., 2007; Ryter et al., 2007). This review formed during metabolism exceed cellular antioxidant capacity discusses the therapeutic application of the BR/BV in disease, as (Davies, 1995). Although ROS act as mediators of cellular homeo- well as clinical data on the role of endogenous BR as an inverse static regulation and signaling (Forman et al., 2010), excessive ROS risk factor for CVD. production may contribute to the pathogenesis of human diseases, including cancer, and cardiovascular diseases (CVD; Drge, 2002; ORIGIN AND METABOLIC FATE OF BILIRUBIN Valko et al., 2006; Sugamura and Keaney, 2011). Cells contain Bilirubin formed in vivo originates from hemoglobin turnover water and lipid soluble chemicals and antioxidant enzymes that (80%) during the degradation of erythrocytes by reticuloen- function to limit harmful oxidative reactions and preserve tissue dothelial macrophages. The remainder of BR formation results homeostasis (Halliwell and Gutteridge, 1999; Davies, 2000). Addi- from hemoprotein turnover in systemic tissues. Biliverdin-IX tionally, many dietary substances can be absorbed and serve as (BV-IX), the precursor to BR, is a water soluble pigment that systemic antioxidants (Kaliora et al., 2006; Garca-Lafuente et al., originates during heme degradation catalyzed by heme oxygenase 2009). Thus, much research has been directed toward the exploita- activity (HO; E.C. 1:14:99:3), represented by constitutive (HO-2) tion of naturally occurring antioxidant compounds as therapeutics and inducible (HO-1) isozymes (Tenhunen et al., 1969; Maines, in the prevention or treatment of human disease (Kaliora et al., 1997). 2006; Garca-Lafuente et al., 2009; Sugamura and Keaney, 2011). Heme oxygenase activity, the rate-limiting step in heme degra- The bile pigments biliverdin (BV) and bilirubin (BR) origi- dation, requires three moles O2 per heme oxidized, and electrons nate as the products of heme degradation (Roy-Chowdhury et al., from NADPH cytochrome-p450 reductase (Yoshida and Kikuchi, 2008; Figure 1). These pigments have been regarded by the medical 1974; Noguchi et al., 1979; Yoshida et al., 1980). Each mole of community as waste products of metabolism (Vitek and Ostrow, BV-IX formed yields one mole each of carbon monoxide (CO), 2009). However, BV/BR exhibit antioxidant properties in model derived from the heme -methene carbon, and ferrous iron (Ten- systems (Stocker et al., 1987a). Circulating BR acts as a potent hunen et al., 1969). BV-IX is reduced to bilirubin-IX (BR-IX), serum antioxidant, and serves as a natural anti-atherogenic fac- a lipid soluble pigment, by NADH/NADPH-dependent biliverdin tor (Stocker et al., 1987b). Retrospective and prospective clinical reductase (BVR; E.C.; Tenhunen et al., 1970). studies indicate that mildly elevated levels of BR (mild hyper- Bilirubin follows a sequence of biological transformation and bilirubinemia) are associated with reduced CVD risk (Franchini elimination steps (Figure 2). BR formed in situ passes to the et al., 2010). Benecial effects of pharmacological BR/BV have serum where it circulates in a complex with serum albumin (Roy- been described in pre-clinical models of tissue injury and disease, Chowdhury et al., 2008; Vitek and Ostrow, 2009). A fraction March 2012 | Volume 3 | Article 39 | 1

2 Ryter Therapeutic applications of bilirubin FIGURE 1 | Sequence of bile pigment formation and degradation. Heme biliverdin reductase (BVR). BR is conjugated with glucuronic acid at its Oxygenase (HO) degrades heme to biliverdin-IX (BV), in a reaction propionyl side chains by hepatic UDP-glucuronyltransferase-1A1 (UGT1A1), to generating carbon monoxide (CO) and ferrous iron, at the expense of NADPH form BR mono- and di-glucuronides. BR can be further metabolized to and molecular oxygen. BV is reduced to bilirubin-IX (BR) by NAD(P)H urobilinogen by intestinal microora. of serum unconjugated BR circulates freely (0.01%; Vitek and challenged with free radical initiating chemicals (Stocker and Ostrow, 2009). Unconjugated BR is taken up by the liver by facili- Ames, 1987; Stocker et al., 1987a; Stocker and Peterhans, 1989a). tated diffusion, involving organic ion transporters (e.g., SLCO1B1; In these model systems, BR and BV exerted chain-breaking and Kamisako et al., 2000; Cui et al., 2001). The intracellular hepatocyte peroxyl radical trapping activity (Stocker and Ames, 1987; Stocker transport of BR is assisted by ligandin, a complex of glutathione- et al., 1987a). BV and conjugated BR acted as co-antioxidants with S-transferase (GST) subunits, and by protein-Z (Litwack et al., -tocopherol, and inhibited -tocopherol consumption (Stocker 1971). BR is conjugated in hepatocytes by uridine diphosphate and Peterhans, 1989a). BR also prevented oxidative damage to pro- (UDP) glucuronyltransferase (UGT1A1; EC:; Chowd- teins, such as serum albumin exposed to ROS-generating systems hury et al., 1979). Conjugated BR (mono- and di-glucuronides) (Stocker et al., 1987b; Neuzil and Stocker, 1993). Free and albumin- is pumped from hepatocytes across the canalicular membrane bound BR inhibited oxidation of LDL-bound lipids, by acting as by multidrug resistance protein-2 and excreted through the bile co-antioxidants with the LDL-bound -tocopherol (Neuzil and to the intestine (Chowdhury and Chowdhury, 1983; Wang et al., Stocker, 1994). 2006a). Bilirubin can react with superoxide anion radical, hypochlorous acid, and singlet molecular oxygen, inhibit the photo-oxidation of ANTIOXIDANT EFFECTS OF BILE PIGMENTS protein, and inhibit chemiluminescence in activated macrophages The potential for the use of bile pigments as therapeutics orig- (Stevens and Small, 1976; Pedersen et al., 1977; Stocker and Peter- inated with the discovery that these substances act as natural hans, 1989b). BR can also react with NO or reactive nitrogen antioxidants. Stocker et al. demonstrated that BV, BR, and con- species (RNS; Kaur et al., 2003; Mancuso et al., 2003). Finally, con- jugated BR inhibit lipid peroxidation in liposomal preparations jugated BR forms a cupric complex that promotes decomposition Frontiers in Pharmacology | Drug Metabolism and Transport March 2012 | Volume 3 | Article 39 | 2

3 Ryter Therapeutic applications of bilirubin antioxidant function is unknown. A common argument against a cellular antioxidant role for BR is that the cellular milieu contains efcient and abundant endogenous antioxidant com- pounds, including millimolar quantities of reduced glutathione (GSH; Meister and Anderson, 1983), ascorbate, -carotene, and -tocopherol (Halliwell and Gutteridge, 1999). Given that BR is exported and eliminated, the relative contribution of BR to cel- lular antioxidant capacity in the presence of other endogenous antioxidants remains unclear. Current evidence for the role of BR as a cellular antioxidant is based on evidence using siRNA studies targeting BVR, the enzyme responsible for BR formation. Knockdown of BVR sensitized cells to high concentrations of H2 O2 (Baranano et al., 2002), and to arsenite-mediated apoptosis (Miralem et al., 2005). In the latter case, similar effects were not achieved with HO-1 knockdown, suggesting effects of BVR independent of BR generation (Miralem et al., 2005). Snyder et al. observed that BV is formed during the oxidation of FIGURE 2 | Biodistribution of BR. BR is generated in systemic tissues as BR (Baranano et al., 2002). The authors proposed that BV formed the product of hemoprotein (i.e., hemoglobin) degradation. BR formed in by BR oxidation would act as a substrate for BVR, to regener- tissues passes freely to the circulation, where it exists mostly in a complex ate BR, and thus represent a self-perpetuating antioxidant system, with serum albumin. BR is taken up by hepatocytes by facilitated diffusion. In the hepatocyte, BR is transported by glutathione-S-transferase (GST), the BVR antioxidant cycle. Evidence for and against this path- and then conjugated by UDP-glucuronyltransferase-1A1 (UGT1A1) to form way has been debated elsewhere (Maghzal et al., 2009; Sedlak and bilirubin di-glucuronide (BR-dG). Conjugated BR (BR-dG) is then pumped Snyder, 2009; Stocker and Maghzal, 2009). It remains unclear if into the bile duct and reaches the intestine. Conjugated BR can be BV regenerated during the oxidation of BR would exceed but a reabsorbed in the intestine and re-enter the circulation (Roy-Chowdhury et al., 2008; Vitek and Ostrow, 2009). The metabolism of BR in the intestine minor fraction, and whether this would contribute signicantly to by bacterial action generates urobilinogen (UB) and its oxidation product cellular antioxidant capacity as proposed. urobilin, the latter which is eliminated in the feces. Intestinal urobilinogen can be reabsorbed by the intestine and eliminated in the urine as urobilin TOXICITY OF BILIRUBIN (Chowdhury and Chowdhury, 1983; Wang et al., 2006a). Bilirubin accumulation can be harmful, especially in infants with neonatal hyperbilirubinemia. The selective toxicity of BR to the neonate is due to incomplete establishment of the bloodbrain of hydroperoxides, representing a pro-oxidant activity in the bile barrier. Neonatal unconjugated hyperbilirubinemia is associated (Stocker and Ames, 1987). with severe neurological side effects, which include neurologi- Bilirubin serves as circulating antioxidant in human plasma. cal encephalopathy and kernicterus (Vitek and Ostrow, 2009). To The treatment of plasma with oxidizing agents resulted in the avoid risk of neurotoxicity, phototherapy is applied to reduce the depletion of endogenous antioxidants in the order ubiquinol-10, levels of unconjugated BR in jaundiced newborns (Blanckaert and ascorbate, and bilirubin. The addition of BR to human plasma Fevery, 1990). The mechanisms of BR toxicity in the brain have after depletion of naturally occurring antioxidants resulted in the been reviewed elsewhere (Brito et al., 2008; Ghersi-Egea et al., inhibition of lipid peroxidation, and reduction of -tocopherol 2009; Tell and Gustincich, 2009; Vitek and Ostrow, 2009). consumption (Neuzil and Stocker, 1994). Serum samples from hyperbilirubinemic patients with Gilberts syndrome were resis- PROTECTIVE EFFECTS OF BILE PIGMENTS IN ANIMAL MODELS OF tant to oxidation and displayed higher total antioxidant capacity TISSUE INJURY than serum from subjects in the normal range of BR concentration Excluding neonatal toxicity, mild hyperbilirubinemia, due to ele- (Bulmer et al., 2008). vated serum antioxidant capacity, may confer benets to the host. Exogenous BR when applied pharmacologically to cultured In a mouse model of hyperbilirubinemia, jaundiced Gunn rats cells can provide dose-dependent cytoprotection against oxidative displayed lower indices of oxidative stress in the serum than stress (Clark et al., 2000a). For example, BR (15 M) protected wild-type mice when challenged with hyperoxia (Dennery et al., cultured vascular smooth muscle cells against cytotoxicity from 1995). enzyme-generated H2 O2 (Clark et al., 2000a). BR when applied Therapeutic application of BR preserved myocardial function at nanomolar concentrations protected primary neurons against during cardiac ischemia/reperfusion (I/R) injury (Clark et al., cytotoxicity caused by exogenous H2 O2 (Dor et al., 1999). 2000b). In an isolated perfused heart model, heme precondition- Despite evidence suggesting that extracellular BR can act as a ing protected against myocardial infarction following I/R injury, cytoprotectant, the role of BR as a cellular antioxidant remains associated with increased HO-1 expression and BR formation. unclear. BR produced in situ is secreted to the circulation, conju- Administration of BR at nanomolar concentrations improved car- gated in the liver, and excreted (Roy-Chowdhury, 1996). However, diac performance and reduced infarct size and mitochondrial the fraction of BR that is retained in cells to serve a membrane dysfunction following I/R injury (Clark et al., 2000b) March 2012 | Volume 3 | Article 39 | 3

4 Ryter Therapeutic applications of bilirubin Injection of BV decreased pro-inammatory cytokines inclusion of BV in the perfusate increased survival in rats subjected production (i.e., IL-6), upregulated IL-10 levels, and reduced to orthotopic liver transplantation by preserving liver function inammatory lung injury in rats challenged with lipopolysac- (Fondevila et al., 2004). This protection conferred by BV was asso- charide (LPS). Thus, BV protected against systemic inamma- ciated with decreased expression of pro-inammatory indices, tion and lung injury after lethal exposure to LPS. The protective including neutrophil inux, pro-inammatory cytokine expres- effects of BV against LPS-induced injury were observed in cul- sion, and iNOS activation (Fondevila et al., 2004). BV treatment tured lung endothelial cells and macrophages (Sarady-Andrews improved survival of rat cardiac allografts, by reducing leukocyte et al., 2005). Additional anti-inammatory effects of BR have been inltration and inhibiting T-cell proliferation (Yamashita et al., reported in cell culture. For example, BR inhibited TNF- depen- 2004). In transplant-associated cold I/R injury of heart and kid- dent expression of adhesion molecules (i.e., E-selectin, VCAM-1, ney grafts, the application of BV simultaneously with CO provided ICAM-1) in endothelial cells (Mazzone et al., 2009). Recently, a synergistic tissue protection, whereas lesser effects were observed enhanced nuclear translocation of BVR has been implicated in with either test agent alone (Nakao et al., 2000). BV also prevented the anti-inammatory effects of BV (Wegiel et al., 2011). rejection of lung grafts from brain-dead donors, which are more Bilirubin can act as an inhibitor of smooth muscle cell pro- prone to rejection (Zhou et al., 2011). In allogeneic islet trans- liferation (Nakao et al., 2005; Ollinger et al., 2005). Exogenous plantation, treatment of the donor or the donor graft ex vivo with BV administration inhibited neointimal hyperplasia associated BR improved islet graft survival. Treatment of the recipient with with vascular injury in rats (Nakao et al., 2005; Ollinger et al., BR also improved the survival of islet grafts (Wang et al., 2006b; 2005). These effects were attributed to downregulation of JNK, Zhu et al., 2010). BR conferred transplant tolerance to islet grafts and inhibition of endothelial cell apoptosis (Nakao et al., 2005). by up-regulating regulatory T cells (Lee et al., 2007). The anti- Similarly, hyperbilirubinemic animals were resistant to vascular apoptotic and anti-inammatory effects of BV/BR observed in I/R injury (Ollinger et al., 2005). The anti-proliferative effects of BV injury models may contribute to protection during I/R injury asso- and BR were demonstrated in vascular smooth muscle cell culture. ciated with transplantation. These experiments also suggest that Exogenous BV/BR arrested cells in G1 phase after serum stimula- pharmacological BR may have immunomodulatory functions that tion, associated with inhibition of p38 MAPK and retinoblastoma contribute to therapeutic effects in the setting of graft rejection protein phosphorylation (Ollinger et al., 2005). (Ollinger et al., 2007). Experimental hyperbilirubinemia (310 mg/dl) induced by infusion protected against bleomycin-induced pulmonary bro- BILIRUBIN IN CARDIOVASCULAR AND LUNG DISEASE sis in rats (Wang et al., 2002). BR-infused rats displayed reduced Recent clinical studies have reported inverse associations between lung injury in response to bleomycin challenge, including lowered serum BR levels and the risk factors associated with CVD. These lung hydroxyproline content, reduced polymorphonuclear lym- studies collectively suggest that natural elevations in serum BR phocyte and leukocyte counts, and reduced levels of transforming confer protection against CVD, including atherosclerosis, coro- growth factor- in bronchoalveolar lavage (Wang et al., 2002). nary artery disease (CAD)/ischemic heart disease (IHD), diabetes, Thus, the anti-brotic effects of BR may relate to both antioxidant and stroke (Novotn and Vtek, 2003; Franchini et al., 2010). and anti-proliferative effects of this pigment. In one of the rst studies reporting associations between BR Recent studies have also implied a protective effect of BV/BR and CVD, a study of 619 males adjusted for age-dependent risk in diabetes. Application of BV to streptozotocin induced diabetic factors, the level of serum BR was described as an inverse risk fac- rats reduced urinary isoprostanes, and protected against endothe- tor for CAD (Schwertner et al., 1994). BR was weakly predictive lial cell sloughing (Rodella et al., 2006). BR ameliorated diabetic for CAD relative to lipoprotein markers (Levinson, 1997). Never- nephropathy, through the reduction of cytosolic ROS generation theless, a strong correlation between BR levels and apolipoprotein and anti-inammatory effects (Fujii et al., 2010). Hyperbiliru- B levels, a risk factor for atherosclerosis, was reported (Levinson, binemic mice, or BV-treated diabetic mice, displayed reduced 1997). Serum BR levels represented an inverse risk factor for CAD albuminuria, and urinary markers of oxidative stress relative to in subjects with early familial CAD (Hopkins et al., 1996). wild-type or untreated controls, respectively. Application of BV or In a large-scale prospective study (7,685 men), subjects in the BR inhibited ROS production in endothelial and mesangial cells midrange of serum BR concentration displayed reduced risk of induced by high glucose or angiotensin-II exposure (Fujii et al., IHD, relative to subjects in the lowest quintile of serum BR distri- 2010). bution (Breimer et al., 1995). Individuals in the lowest BR quintile exhibited reduced high density lipoprotein (HDL) cholesterol, and PROTECTIVE EFFECTS OF BILE PIGMENTS IN ORGAN reduced lung function. Although midlevel serum BR was associ- TRANSPLANTATION ated with reduced CVD risk, the hyperbilirubinemic individuals Therapeutic effects of exogenously applied bile pigments have (highest quintile) exhibited a similar risk of IHD as individuals in been described in animal models of organ transplantation and the lowest serum BR quintile (Breimer et al., 1995). acute graft rejection, including liver (Fondevila et al., 2004), kidney Serum BR levels have been indicated as an independent, inverse (Adin et al., 2005), and heart (Yamashita et al., 2004) trans- risk factor for peripheral vascular disease (Breimer et al., 1994). In plantation. In the isolated perfused kidney, perfusion with BR large-scale cross-sectional studies, serum BR levels within the nor- protected against warm I/R-induced tissue injury and preserved mal range were inversely associated with risk of peripheral vascular renal function (Adin et al., 2005). BV provided tissue protec- disease (Perlstein et al., 2008a) and stroke (Perlstein et al., 2008b). tion in an ex vivo model of cold hepatic I/R injury. Furthermore, A 1.71 M increase in BR level was associated with 6% reduction Frontiers in Pharmacology | Drug Metabolism and Transport March 2012 | Volume 3 | Article 39 | 4

5 Ryter Therapeutic applications of bilirubin in the odds of peripheral vascular disease (7,075 participants; Perl- patients relative to the general population (Vtek et al., 2002). stein et al., 2008a), and 9% reduction in the odds of stroke (13,214 In Gilberts patients, unconjugated BR was negatively correlated participants; Perlstein et al., 2008b). with small dense low density lipoprotein cholesterol sd-LDL-C, In 72 healthy subjects, serum BR levels were inversely corre- oxidized LDL and hs-CRP (Tapan et al., 2011). lated with indicators for atherosclerosis (Erdogan et al., 2005). In the Framingham Heart study homozygote carriers for the Low serum BR levels were associated with increased carotid artery UGT1A128 allele with elevated serum BR concentrations dis- intimal-medial thickness, and impaired ow-mediated vasodila- played a strong association with lower CVD risk (Lin et al., 2006). tion, indicative of endothelial dysfunction (Erdogan et al., 2005). These observations were further validated by conditional linkage Furthermore, BR levels were inversely correlated to carotid plaque and genome-wide association studies. These studies concluded formation in 1,774 subjects, with a reported odds ratio of 0.37 for that UTG1A is a major gene linked to CVD, and that the TA repeat an increase of 17.1 M increase in BR (Ishizaka et al., 2001). polymorphism is strongly associated with reduced CVD risk (Lin In a cross-sectional study of 2,307 Koreans, total and direct BR et al., 2009). In a study of peripheral arterial disease, no association levels were inversely correlated to plasma levels of C-reactive pro- of UGT1A1 polymorphisms was observed, despite inverse corre- tein (CRP), an indicator of vascular inammation (Hwang et al., lation of CVD risk with BR levels (Rantner et al., 2008). Recent 2011). Similar inverse associations were reported between BR and post-mortem studies also reported that UGT1A1 polymorphisms levels of high sensitivity (hs)-CRP (Gullu et al., 2005; Yoshino et al., were not correlated with severity of CAD (Papez et al., 2009). 2011). BR was inversely correlated with CVD in patients with Finally, BR was inversely associated with risk of lung disease. hypercholesterolemia, and elevated in patients receiving statins In a cohort study (504,206 subjects) each 0.1-mg/dL increase in (Nolting et al., 2011). BR in males was associated with 9%, and 6% decreases in the A prospective study (Framingham offspring study, 5,124 par- risk of lung cancer, and chronic obstructive pulmonary disease, ticipants) concluded that a higher concentration of total serum respectively (Horsfall et al., 2011). BR was associated with lower risk of CVD in men, with unclear association for women (Djousse et al., 2001). This study revealed CONCLUSION a higher risk of myocardial infarction for both men and women Biliverdin and BR are naturally occurring substances derived from associated with low serum BR and low serum albumin (Djouss heme catabolism that possess antioxidant properties. Further- et al., 2003). more, circulating BR can contribute to serum antioxidant capacity. Bilirubin levels have been examined as an independent predic- In pre-clinical studies, pharmacological application of BR con- tor of CVD mortality. No association was found between serum fers protection against I/R injury, acute lung injury, pulmonary BR and all-cause CVD mortality in a 10 year study of the Belgian brosis, renal injury, and graft rejection. Several limitations of population, although increased BR was associated with reduced the therapeutic applications of bile pigments must be considered. cancer mortality in males (Temme et al., 2001). However, in a Although BV is soluble in aqueous media, BR is lipophilic and recently published study of 1,279 men, BR levels and cardiopul- soluble only in organic solvents, thereby posing challenges for monary tness level was independently and negatively correlated therapeutic delivery. to all-cause and CVD mortality (Ajja et al., 2011). Bilirubin is the by-product of the heme degradation pathway, Additional studies have analyzed potential associations between and thereby may mediate the cytoprotective properties of HO-1 BR levels and CVD-related diseases such as diabetes (Ko et al., (Foresti et al., 2004). Pharmacological or gene therapy approaches 1996; Fukui et al., 2008, 2011; Cheriyath et al., 2010) and metabolic involving the targeted expression of HO-1 are under develop- syndrome (Jo et al., 2011; Kwon et al., 2011). A large cross-sectional ment (Abraham et al., 2007). However, these approaches are not study (15,876 subjects) reported an inverse association between specic for BV/BR generation, since modulation of HO-1 has total BR and diabetes risk (Cheriyath et al., 2010). Patients with pleiotropic effects that impact systemic iron metabolism and CO type II diabetes on hemodialysis displayed an increased risk of generation. Similarly, targeted expression of BVR may affect cel- CVD associated with low serum BR, relative to diabetic patients lular signaling pathways independently of its role in bile pigment not on hemodialysis (Fukui et al., 2011). Serum BR was inversely generation (Kapitulnik and Maines, 2009). Clinical studies have correlated with albuminuria in Type II diabetic patients (Fukui suggested inverse associations between serum BR and CVD risk. et al., 2008). In a Chinese cohort (1,508 subjects), low serum Mild hyperbilirubinemia may reduce CVD risk, but this awaits BR was associated with aberrations in glucose tolerance, and further validation. To date, there remain no practical methodolo- increases in CVD risk factors including triglycerides, very-low gies for inducing hyperbilirubinemia for clinical benet. Despite density lipoprotein, and glycated hemoglobin (Ko et al., 1996). therapeutic benet in animal tissue injury models, the therapeutic Additional studies have examined associations of BR with CVD potential of BR remains untested in humans. in hyperbilirubinemia originating from metabolic disorders of BR metabolism. A TA repeat polymorphism of the UTG1A1 gene ACKNOWLEDGMENTS promoter (designated UGT1A128, or TA7) results in reduced Dr. Ryter wishes to acknowledge current and former colleagues transcription of UTG1A and decit in hepatic BR conjugation who have contributed to some of the referenced works described and clearance (Schwertner and Vtek, 2008). Individuals homozy- herein. Dr. Ryter currently holds a faculty appointment at the gous for UGT1A128 (TA7/TA7) display a hyperbilirubinemia, Brigham and Womens Hospital (BWH), Boston, and is an Adjunct referred to as Gilberts syndrome, relative to wild-type subjects Scientist of the Lovelace Respiratory Research Institute (LRRI), (TA6/TA6) or heterozygotes. A sixfold reduced risk of IHD and Albuquerque, New Mexico. In this capacity, Dr. Ryter received elevated HDL cholesterol was reported in a study of 50 Gilberts salary support from the LRRI/BWH consortium for lung research. March 2012 | Volume 3 | Article 39 | 5

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8 Ryter Therapeutic applications of bilirubin Tell, G., and Gustincich, S. (2009). Vitek, L., and Ostrow, J. D. (2009). Soares, M. P., and Bach, F. H. (2004). Zhu, H., Wang, J., Jiang, H., Ma, Redox state, oxidative stress, and Bilirubin chemistry and metab- Biliverdin, a natural product of Y., Pan, S., Reddy, S., and Sun, molecular mechanisms of protective olism; harmful and protective heme catabolism, induces tolerance X. (2010). Bilirubin protects graft- and toxic effects of bilirubin on cells. aspects. Curr. Pharm. Des. 15, to cardiac allografts. FASEB J. 18, sagainst non-specic inammation- Curr. Pharm. Des.15, 29082914. 28692883. 765767. induced injury in syngeneic intra- Temme, E. H. M., Zhang, J. J., Schouten, Wang, H. D., Yamaya, M., Okinaga, Yoshida, T., and Kikuchi, G. (1974). portal islet transplantation. Exp. E. G., and Kesteloot, H. (2001). S., Jia, Y. X., Kamanaka, M., Taka- Sequence of the reaction of heme Mol. Med. 42, 739748. Serum bilirubin and 10-year mor- hashi, H., Guo, L. Y., Ohrui, catabolism catalyzed by the micro- tality risk in a Belgian population. T., and Sasaki, H. (2002). Biliru- somal heme oxygenase system. FEBS Cancer Causes Control 12, 887894. bin ameliorates bleomycin-induced Lett. 48, 256261. Conict of Interest Statement: The Tenhunen, R., Marver, H. S., and pulmonary brosis in rats. Am. Yoshida, T., Noguchi, M., and Kikuchi, author declares that the research was Schmid, R. (1969). Microsomal J. Respir. Crit. Care Med. 165, G. (1980). Oxygenated form of conducted in the absence of any com- heme oxygenase. Characterization 406411. heme heme oxygenase complex and mercial or nancial relationships that of the enzyme. J. Biol. Chem. 244, Wang, X., Chowdhury, J. R., and requirement for second electron to could be construed as a potential con- 63886394. Chowdhury, N. R. (2006a). Biliru- initiate heme degradation from the ict of interest. Tenhunen, R., Ross, M. E., Marver, H. bin metabolism: applied physiology. oxygenated complex. J. Biol. Chem. S., and Schmid, R. (1970). Reduced Curr. Pediatr. 16, 7074. 255, 44184420. Received: 15 January 2012; paper pending nicotinamide-adenine dinucleotide Wang, H., Lee, S. S., DellAgnello, C., Yoshino, S., Hamasaki, S., Ishida, S., published: 10 February 2012; accepted: phosphate dependent biliverdin Tchipashvili, V., dAvila, J. C., Czis- Kataoka, T., Yoshikawa, A., Oketani, 21 February 2012; published online: 08 reductase: partial purication and madia, E., Chin, B. Y., and Bach, F. H. N., Saihara, K., Okui, H., Shinsato, T., March 2012. characterization. Biochemistry 9, (2006b). Bilirubin can induce toler- Ichiki, H., Kubozono, T., Kuwahata, Citation: Ryter SW (2012) Bile pig- 298303. ance to islet allografts. Endocrinology S., Fujita, S., Kanda, D., Nakazaki, M., ments in pulmonary and vascular Valko, M., Rhodes, C. J., Moncol, J., Iza- 147, 762768. Miyata, M., and Tei, C. (2011). Rela- disease. Front. Pharmacol. 3:39. doi: kovic, M., and Mazur, M. (2006). Wegiel, B., Gallo, D., Csizmadia, E., tionship between bilirubin concen- 10.3389/fphar.2012.00039 Free radicals, metals and antiox- Roger, T., Kaczmarek, E., Harris, tration, coronary endothelial func- This article was submitted to Frontiers idants in oxidative stress-induced C., Zuckerbraun, B. S., and Otter- tion, and inammatory stress in in Drug Metabolism and Transport, a cancer. Chem. Biol. Interact. 160, bein, L. E. (2011). Biliverdin inhibits overweight patients. J. Atheroscler. specialty of Frontiers in Pharmacology. 140. Toll-like receptor-4 (TLR4) expres- Thromb. 18, 403412. Copyright 2012 Ryter. This is an Vtek, L., Jirsa, M., Brodanov, M., sion through nitric oxide-dependent Zhou, H., Qian, H., Liu, J., Zhu, D., Ding, open-access article distributed under the Kalb, M., Marecek, Z., Danzig, V., nuclear translocation of biliverdin W., Pan, P., Jin, D., Wang, J., and Li, terms of the Creative Commons Attribu- Novotn, L., and Kotal, P. (2002). reductase. Proc. Natl. Acad. Sci. W. (2011). Protection against lung tion Non Commercial License, which per- Gilbert syndrome and ischemic U.S.A. 108, 1884918854. graft injury from brain-dead donors mits non-commercial use, distribution, heart disease: a protective effect of Yamashita, K., McDaid, J., Ollinger, R., with carbon monoxide, biliverdin, or and reproduction in other forums, pro- elevated bilirubin levels. Atheroscle- Tsui, T. Y., Berberat, P. O., Usheva, both. J. Heart Lung Transplant. 30, vided the original authors and source are rosis 160, 449456. A., Csizmadia, E., Smith, R. N., 460466. credited. Frontiers in Pharmacology | Drug Metabolism and Transport March 2012 | Volume 3 | Article 39 | 8

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