Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models

Marlies Wallner; Nadja Antl; Barbara Rittmannsberger; Stephanie Schreidl; Khatereh Najafi; Elisabeth Müllner; Christine Mölzer; Franziska Ferk; Siegfried Knasmüller; Rodrig Marculescu; Daniel Doberer; Henrik E Poulsen; Libor Vitek; Andrew C Bulmer; Karl-Heinz Wagner

doi:10.1158/1940-6207.capr-13-0125

Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models

Marlies Wallner, Nadja Antl, Barbara Rittmannsberger, Stephanie Schreidl, Khatereh Najafi, Elisabeth Müllner, Christine Mölzer, Franziska Ferk, Siegfried Knasmüller, Rodrig Marculescu, Daniel Doberer, Henrik E Poulsen, Libor Vitek, Andrew C Bulmer, Karl-Heinz Wagner

Department of Clinical Medicine

22 Citations (Scopus)

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-oxoguanosine (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/m² (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.

Original language	English
Journal	Cancer Prevention Research
Volume	6
Issue number	10
Pages (from-to)	1056-1063
Number of pages	8
ISSN	1940-6207
DOIs	https://doi.org/10.1158/1940-6207.capr-13-0125
Publication status	Published - Oct 2013

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Wallner, M., Antl, N., Rittmannsberger, B., Schreidl, S., Najafi, K., Müllner, E., Mölzer, C., Ferk, F., Knasmüller, S., Marculescu, R., Doberer, D., Poulsen, H. E., Vitek, L., Bulmer, A. C., & Wagner, K-H. (2013). Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models. Cancer Prevention Research, 6(10), 1056-1063. https://doi.org/10.1158/1940-6207.capr-13-0125

Wallner, M, Antl, N, Rittmannsberger, B, Schreidl, S, Najafi, K, Müllner, E, Mölzer, C, Ferk, F, Knasmüller, S, Marculescu, R, Doberer, D, Poulsen, HE, Vitek, L, Bulmer, AC & Wagner, K-H 2013, 'Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models', Cancer Prevention Research, vol. 6, no. 10, pp. 1056-1063. https://doi.org/10.1158/1940-6207.capr-13-0125

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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-oxoguanosine (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/m2 (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.",

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T2 - Damage to DNA in Hyperbilirubinemic Human and Animal Models

AU - Wallner, Marlies

AU - Antl, Nadja

AU - Rittmannsberger, Barbara

AU - Schreidl, Stephanie

AU - Najafi, Khatereh

AU - Müllner, Elisabeth

AU - Mölzer, Christine

AU - Ferk, Franziska

AU - Knasmüller, Siegfried

AU - Marculescu, Rodrig

AU - Doberer, Daniel

AU - Poulsen, Henrik E

AU - Vitek, Libor

AU - Bulmer, Andrew C

AU - Wagner, Karl-Heinz

PY - 2013/10

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N2 - 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-oxoguanosine (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/m2 (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.

AB - 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-oxoguanosine (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/m2 (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.

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DO - 10.1158/1940-6207.capr-13-0125

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JO - Cancer Prevention Research

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ER -

Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models

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