Enhanced carbonyl stress in a subpopulation of schizophrenia

Makoto Arai, Hiroko Yuzawa, Izumi Nohara, Tetsuo Ohnishi, Nanako Obata, Yoshimi Iwayama, Seiichi Haga, Tomoko Toyota, Hiroshi Ujike, Mayumi Arai, Tomoe Ichikawa, Atsushi Nishida, Yoko Tanaka, Aizo Furukawa, Yuuzou Aikawa, Osamu Kuroda, Kazuhiro Niizato, Ryosuke Izawa, Kazuhiko Nakamura, Norio MoriDaisuke Matsuzawa, Kenji Hashimoto, Masaomi Iyo, Ichiro Sora, Masaaki Matsushita, Yuji Okazaki, Takeo Yoshikawa, Toshio Miyata, Masanari Itokawa

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)

Abstract

Context: Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B 6 is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. Objectives: To examine whether plasma levels of pentosidine and serum vitamin B6 are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. Design: An observational biochemical and genetic analysis study. Setting: Multiple centers in Japan. Participants: One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. Main Outcome Measures: Pentosidine and vitamin B6 concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. Results: We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B6) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B6 depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B6 levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. Conclusions: Our findings suggest thatGLO1deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B6 levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes.

Original languageEnglish
Pages (from-to)589-597
Number of pages9
JournalArchives of General Psychiatry
Volume67
Issue number6
DOIs
Publication statusPublished - 2010 Jun

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

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