Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterised by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt haemolytic disease. However, since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as multiple intracellular signalling pathways affected by bilirubin, an ever-increasing body of evidence suggests that individuals with Gilbert's syndrome may benefit from the mild hyperbilirubinaemia and are actually protected from the development of a wide variety of "diseases of civilisation" such as cardiovascular diseases, certain cancers, and autoimmune or neurodegenerative diseases. This review analyses the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and provides a new perspective on this condition.
- MeSH
- antioxidancia MeSH
- bilirubin metabolismus MeSH
- Gilbertova nemoc * metabolismus MeSH
- hyperbilirubinemie metabolismus MeSH
- játra metabolismus MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions.
- MeSH
- antioxidancia metabolismus MeSH
- bilirubin metabolismus MeSH
- diabetes mellitus metabolismus MeSH
- hyperbilirubinemie metabolismus MeSH
- kardiovaskulární nemoci metabolismus MeSH
- lidé MeSH
- nádory metabolismus MeSH
- nemoci nervového systému metabolismus MeSH
- oxidace-redukce MeSH
- oxidační stres MeSH
- signální transdukce * MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
AIM: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. METHODS: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia. RESULTS: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). CONCLUSIONS: Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
- MeSH
- bilirubin krev MeSH
- biologické markery krev MeSH
- cholestáza diagnóza genetika metabolismus MeSH
- down regulace MeSH
- fixace tkání metody MeSH
- fixativa MeSH
- formaldehyd MeSH
- hepatocyty metabolismus patologie MeSH
- hyperbilirubinemie diagnóza genetika metabolismus MeSH
- imunohistochemie MeSH
- játra metabolismus patologie MeSH
- lidé MeSH
- myši transgenní MeSH
- přenašeče organických aniontů nezávislé na sodíku genetika metabolismus MeSH
- přenašeče organických aniontů genetika metabolismus MeSH
- retrospektivní studie MeSH
- zalévání tkání do parafínu MeSH
- zmrazené řezy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Antioxidant, anti-inflammatory and anti-atherogenic effects have been associated with elevations of unconjugated bilirubin (UCB) in serum and with the induction of heme oxygenase-1 (HO-1), the rate-limiting enzyme in UCB synthesis. The aim of this study was to investigate the intracellular metabolism and antioxidant properties of UCB in human hepatoblastoma HepG2 cells and tissues of Wistar rats exposed to oxidative stressors and lipopolysaccharide (LPS), respectively. Intracellular UCB concentrations in HepG2 cells correlated with its levels in culture media (p < 0.001) and diminished lipid peroxidation in a dose-dependent manner (p < 0.001). Moreover, induction of HO-1 with sodium arsenite led to 2.4-fold (p = 0.01) accumulation of intracellular UCB over basal level while sodium azide-derived oxidative stress resulted in a 60% drop (p < 0.001). This decrease was ameliorated by UCB elevation in media or by simultaneous induction of HO-1. In addition, hyperbilirubinemia and liver HO-1 induction in LPS-treated rats resulted in a 2-fold accumulation of tissue UCB (p = 0.01) associated with enhanced protection against lipid peroxidation (p = 0.02). In conclusion, hyperbilirubinemia and HO-1 induction associated with inflammation and oxidative stress increase intracellular concentrations of UCB, thus enhancing the protection of cellular lipids against peroxidation. Therefore, the previously reported protective effects of hyperbilirubinemia and HO-1 induction are at least in part due to intracellular accumulation of UCB.
- MeSH
- aktivace enzymů účinky léků MeSH
- antioxidancia metabolismus MeSH
- arsenitany farmakologie MeSH
- bilirubin aplikace a dávkování analogy a deriváty metabolismus MeSH
- buňky Hep G2 MeSH
- hem analýza MeSH
- hemoxygenasa-1 metabolismus MeSH
- hyperbilirubinemie metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lipopolysacharidy aplikace a dávkování MeSH
- methemalbumin farmakologie MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- potkani Wistar MeSH
- sloučeniny sodíku farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
1. elektronické vydání 1 online zdroj (136 stran)
Cílem předkládané publikace je shrnout současné poznatky v této rychle se rozvíjející oblasti a nastínit další možné klinické konsekvence. Jedná se zejména o vztah bilirubinu k onemocněním podmíněných oxidačním stresem, jako jsou kardiovaskulární nemoci, nádorová či revmatologická onemocnění.Publikace řeší oproti ostatním publikacím na trhu, kterých je minimálně, nový přístup k tematice - neopomíjí moderní poznatky, a ustupuje tedy od tradičního pojetí, zabývá se i interdisciplinárním významem poruch metabolismu bilirubinu, epidemiologií chorob podmíněných oxidačním stresem ve vztahu k hladinám bilirubinu apod.Kniha je určena zejména gastroenterologům, hepatologům, internistům, ale i praktickým lékařům, studentům medicíny i široké odborné veřejnosti.
Unconjugated bilirubin (UCB), the principal mammalian bile pigment, is the end product of heme catabolism. Both belong to the superfamily of tetrapyrrolic compounds that serve multiple biological functions in animals and plants. Its six internal hydrogen bonds give UCB a unique structure responsible for its physico-chemical properties and biological effects. Like many weakly-polar, poorly-soluble compounds, UCB is transported in blood tightly bound to albumin, with less than 0.01% of total bilirubin circulating in an unbound form (free bilirubin, Bf). This fraction governs the diffusion of UCB into tissues, and therefore Bf is responsible for both its beneficial and toxic effects on cells. Although, UCB was long thought to be a non-functional waste product, recent studies have shown that the antioxidant effects of mildly elevated serum bilirubin levels, as well as activation of heme oxygenase, may protect against diseases associated with oxidative stress, such as atherosclerosis. By contrast, markedly elevated serum UCB levels may cause severe neurological damage, especially in neonates. The regulation of cellular UCB content, by its conjugation, oxidation, and export, are, therefore of paramount importance to cellular health.
- MeSH
- bilirubin chemie krev metabolismus MeSH
- biologický transport MeSH
- hem metabolismus MeSH
- hyperbilirubinemie komplikace metabolismus MeSH
- játra metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- nemoci centrálního nervového systému etiologie metabolismus MeSH
- novorozenec MeSH
- novorozenecká hyperbilirubinemie komplikace metabolismus MeSH
- oxidace-redukce MeSH
- oxidační stres MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
1. vyd. xii, 123 s. : il., tab. ; 25 cm
- MeSH
- bilirubin metabolismus MeSH
- cholelitiáza diagnóza etiologie terapie MeSH
- Criglerův-Najjarův syndrom metabolismus terapie MeSH
- experimenty na zvířatech MeSH
- hladovění metabolismus MeSH
- hyperbilirubinemie etiologie metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- novorozenecká hyperbilirubinemie etiologie metabolismus MeSH
- primární prevence MeSH
- probiotika metabolismus terapeutické užití MeSH
- sloučeniny zinku metabolismus MeSH
- střeva metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- MeSH
- bilirubin chemie metabolismus škodlivé účinky MeSH
- Criglerův-Najjarův syndrom metabolismus MeSH
- enterohepatická cirkulace MeSH
- finanční podpora výzkumu jako téma MeSH
- hyperbilirubinemie metabolismus MeSH
- lidé MeSH
- novorozenecká žloutenka metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
