Enhanced carbonyl stress in a subpopulation of schizophrenia.
BACKGROUND
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.


OBJECTIVE
To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress.


METHODS
An observational biochemical and genetic analysis study.


METHODS
Multiple centers in Japan.


METHODS
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.


METHODS
Pentosidine and vitamin B(6) 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 B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms.


CONCLUSIONS
Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) 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.
Project for Schizophrenia Research, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya, Tokyo, Japan.
Makoto
M
Arai
Hiroko
H
Yuzawa
Izumi
I
Nohara
Tetsuo
T
Ohnishi
Nanako
N
Obata
Yoshimi
Y
Iwayama
Seiichi
S
Haga
Tomoko
T
Toyota
Hiroshi
H
Ujike
Mayumi
M
Arai
Tomoe
T
Ichikawa
Atsushi
A
Nishida
Yoko
Y
Tanaka
Aizo
A
Furukawa
Yuuzou
Y
Aikawa
Osamu
O
Kuroda
Kazuhiro
K
Niizato
Ryosuke
R
Izawa
Kazuhiko
K
Nakamura
Norio
N
Mori
Daisuke
D
Matsuzawa
Kenji
K
Hashimoto
Masaomi
M
Iyo
Ichiro
I
Sora
Masaaki
M
Matsushita
Yuji
Y
Okazaki
Takeo
T
Yoshikawa
Toshio
T
Miyata
Masanari
M
Itokawa
D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D012559:Schizophrenia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D025101:Vitamin B 6 / Q000097:blood*
D015415:Biomarkers; D017127:Glycation End Products, Advanced; D025101:Vitamin B 6; D001120:Arginine; C062187:pentosidine; D007791:Lactoylglutathione Lyase; D008239:Lysine