title: Anti-genotoxic potential of bilirubin in vivo: damage to DNA in hyperbilirubinemic human and animal models.
abstract: The bile pigment bilirubin is a known antioxidant and is associated with protection from cancer and cardiovascular disease (CVD) when present in too strong concentrations. Unconjugated bilirubin (UCB) might also possess anti-genotoxic potential by preventing oxidative damage to DNA. Moderately elevated bilirubin levels are found in individuals with Gilbert syndrome and more severe in the hyperbilirubinemic Gunn rat model. This study was therefore aimed to assess the levels of oxidative damage to DNA in Gilbert syndrome subjects and Gunn rats compared to matched controls. Seventy-six individuals (age- and sex-matched) were allocated into Gilbert syndrome (UCB ≥17.1 μmol/L; n = 38) or control groups (UCB < 17.1 μmol/L; n = 38). In addition, 40 Gunn rats were used to support the results of the human trial. Single-cell gel electrophoresis (SCGE) assay measuring standard conditions (strand breaks, apurinic/apyrimidinic sites) and formamidopyrimidine glycosylase (FPG)-sensitive sites was conducted in human peripheral blood mononuclear cells (PBMC) and rat PBMCs, colon, and hepatocytes. Furthermore, urinary 8-oxo-2'-deoxyguanosine (8oxodGuo, DNA oxidation) and 8-oxo-guanosine (8oxoGuo, RNA oxidation) were measured in humans. The Gilbert syndrome and Gunn rat groups had significantly higher UCB levels (P < 0.001) than the corresponding controls. No further differences in damage to DNA or RNA were detected between the two groups, except higher strand breaks (PBMCs) in Gunn rats when compared with controls. However, when demographic effects were analyzed, lower 8oxodGuo concentrations were detected in the human group with a BMI ≥25 kg/m(2) (1.70 ± 0.67 vs. 1.38 ± 0.43 nmol/mmol creatinine, P < 0.05), although this group showed lower UCB levels than normal weight subjects. This study suggests that the disease preventative effect of UCB is unrelated to DNA oxidation/strand breaks in human and animal models of hyperbilirubinaemia.
authors: Department of Nutritional Science, University of Vienna, Althanstraße 14, Vienna 1090, Austria. karl-heinz.wagner@univie.ac.at.
authors: Marlies
authors: M
authors: Wallner
authors: Nadja
authors: N
authors: Antl
authors: Barbara
authors: B
authors: Rittmannsberger
authors: Stephanie
authors: S
authors: Schreidl
authors: Khatereh
authors: K
authors: Najafi
authors: Elisabeth
authors: E
authors: Müllner
authors: Christine
authors: C
authors: Mölzer
authors: Franziska
authors: F
authors: Ferk
authors: Siegfried
authors: S
authors: Knasmüller
authors: Rodrig
authors: R
authors: Marculescu
authors: Daniel
authors: D
authors: Doberer
authors: Henrik E
authors: HE
authors: Poulsen
authors: Libor
authors: L
authors: Vitek
authors: Andrew C
authors: AC
authors: Bulmer
authors: Karl-Heinz
authors: KH
authors: Wagner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016587:Antimutagenic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry; D001663:Bilirubin / Q000737:chemistry*; D015992:Body Mass Index; D016022:Case-Control Studies; D020552:Comet Assay; D003404:Creatinine / Q000097:blood; D004249:DNA Damage; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D005878:Gilbert Disease / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology; D006710:Homocysteine / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000737:chemistry; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D055815:Young Adult
chemical_list: D016587:Antimutagenic Agents; D000975:Antioxidants; D009153:Mutagens; D006710:Homocysteine; D003404:Creatinine; D043382:DNA-Formamidopyrimidine Glycosylase; D001663:Bilirubin; D010100:Oxygen