title: Evidence for increased oxidative stress in peroxisomal D-bifunctional protein deficiency.
abstract: Peroxisome biogenesis disorders (PBDs) and D-bifunctional protein (D-BP) deficiency are two types of inherited peroxisomal disorders. Patients with a PBD lack functional peroxisomes and patients with D-BP deficiency lack the enzyme, which is responsible for the second and third step of the peroxisomal beta-oxidation. The clinical presentation of these peroxisomal disorders is severe and includes several neurological abnormalities. The pathological mechanisms underlying these disorders are not understood and no therapies are available. Because peroxisomes have been associated with oxidative stress, as oxygen radicals are both produced and scavenged in peroxisomes, we have investigated whether oxidative stress is involved in the pathogenesis of PBDs and D-BP deficiency. We found in D-BP-deficient patients increased levels of thiobarbituric acid-reactive substances (TBARS) and 8-hydroxydeoxyguanosine (8-OHdG), which are markers for lipid peroxidation and oxidative DNA damage, respectively, whereas the levels of the lipophilic antioxidants alpha-tocopherol and coenzyme Q(10) were decreased. In addition, we found in skin fibroblasts from D-BP-deficient patients an imbalance between the activities of the peroxisomal H(2)O(2)-generating straight-chain acyl-CoA oxidase (SCOX) and the peroxisomal H(2)O(2)-degrading enzyme catalase. In conclusion, we have found clear evidence for the presence of increased oxidative stress in patients with D-BP deficiency, but not in patients with a PBD.
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. S.Ferdinandusse@amc.uva.nl
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: Barbara
authors.initials: B
authors.lastname: Finckh
authors.forename: Yvette C
authors.initials: YC
authors.lastname: de Hingh
authors.forename: Lida E M
authors.initials: LE
authors.lastname: Stroomer
authors.forename: Simone
authors.initials: S
authors.lastname: Denis
authors.forename: Alfried
authors.initials: A
authors.lastname: Kohlschütter
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000097:blood / Q000172:deficiency* / Q000652:urine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002460:Cell Line; D003067:Coenzymes; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D004746:Enoyl-CoA Hydratase; D005347:Fibroblasts; D006801:Humans; D006836:Hydro-Lyases / Q000097:blood / Q000172:deficiency* / Q000652:urine; D015227:Lipid Peroxidation; D009097:Multienzyme Complexes / Q000097:blood / Q000172:deficiency* / Q000652:urine; D018384:Oxidative Stress; D018901:Peroxisomal Disorders / Q000097:blood / Q000175:diagnosis* / Q000652:urine; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000201:enzymology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood; D024502:alpha-Tocopherol / Q000032:analysis / Q000097:blood; D024504:gamma-Tocopherol / Q000032:analysis / Q000097:blood
chemical_list: D003067:Coenzymes; D009097:Multienzyme Complexes; D017392:Thiobarbituric Acid Reactive Substances; D014451:Ubiquinone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D024504:gamma-Tocopherol; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D004746:Enoyl-CoA Hydratase; C024989:coenzyme Q10; D003849:Deoxyguanosine; D024502:alpha-Tocopherol