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Differences in glyoxal and methylglyoxal metabolism determine cellular susceptibility to protein carbonylation and cytotoxicity.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2011 May 30; Vol. 191 (1-3), pp. 322-9. Date of Electronic Publication: 2011 Feb 18. - Publication Year :
- 2011
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Abstract
- Chronic hyperglycemia in diabetic patients often leads to chronic side effects associated with protein glycation and the formation of reactive carbonyl species, such as methylglyoxal (MGO) and glyoxal (GO). We have shown that both MGO and GO carbonylated bovine serum albumin (BSA) in vitro to the same degree and stability. The carbonylated BSA formed initially could be a reversible Schiff base as the UV absorbance formed after the addition of 2,4-dinitrophenylhydrazine was decreased when sodium borohydride was added. MGO and GO also carbonylated hepatocyte protein rapidly with similar dose and time dependence. In contrast to BSA carbonylation, the amount of carbonylated proteins in hepatocytes decreased over time, much more rapidly for hepatocytes treated with MGO than with GO. This could be attributed to the rapid hepatocyte metabolism of MGO with glyoxalase I, the predominant detoxification enzyme for MGO. Protein carbonylation and the associated toxicity caused by GO and MGO were studied in the following hepatocyte models: (1) control hepatocytes, (2) glutathione (GSH)-depleted hepatocytes, (3) mitochondrial aldehyde dehydrogenase (ALDH2)-inhibited hepatocytes, (4) hepatocyte inflammation model, and (5) catalase-inhibited hepatocyte model. Carbonylation and cytotoxicity caused by MGO or GO was markedly increased in GSH-depleted hepatocytes as compared to control hepatocytes. Hepatocytes exposed to non-toxic concentrations of H(2)O(2) or hepatocytes treated with catalase inhibitors also showed a marked increase in GO-caused cytotoxicity and protein carbonylation, whereas there were only minor increases with MGO. The GO effect was attributed to potential radical formation and the inhibition effect of H(2)O(2) on aldehyde dehydrogenase, a major GO metabolising enzyme. GO-caused cytotoxicity and protein carbonylation were also increased with ALDH2-inhibited hepatocytes whereas such an increase was only observed with MGO in GSH-depleted hepatocytes.<br /> (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Aldehyde Dehydrogenase antagonists & inhibitors
Aldehyde Dehydrogenase, Mitochondrial
Animals
Cattle
Enzyme Inhibitors pharmacology
Hepatocytes drug effects
Hepatocytes enzymology
Hepatocytes metabolism
Mitochondrial Proteins antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Reducing Agents metabolism
Schiff Bases metabolism
Serum Albumin, Bovine metabolism
Cytotoxins metabolism
Cytotoxins toxicity
Glyoxal metabolism
Glyoxal toxicity
Protein Carbonylation drug effects
Pyruvaldehyde metabolism
Pyruvaldehyde toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 191
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 21334317
- Full Text :
- https://doi.org/10.1016/j.cbi.2011.02.012