Aminophospholipid glycation and its inhibitor screening system: a new role of pyridoxal 5'-phosphate as the inhibitor

Ohki Higuchi^*, Kiyotaka Nakagawa^*, Tsuyoshi Tsuzuki^*, Toshihide Suzuki, Shinichi Oikawa and Teruo Miyazawa¹^,*

^* Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan
Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Department of Medicine, Nippon Medical School, Tokyo 113-8603, Japan

Published, JLR Papers in Press, February 9, 2006.

^¹ To whom correspondence should be addressed. e-mail: miyazawa{at}biochem.tohoku.ac.jp

Peroxidized phospholipid-mediated cytotoxity is involved inthe pathophysiology of a number of diseases [i.e., the abnormalincrease of phosphatidylcholine hydroperoxide (PCOOH) foundin the plasma of type 2 diabetic patients]. The PCOOH accumulationmay relate to Amadori-glycated phosphatidylethanolamine (deoxy-D-fructosylPE, or Amadori-PE), because Amadori-PE causes oxidative stress.However, lipid glycation inhibitor has not been discovered yetbecause of the lack of a lipid glycation model useful for inhibitorscreening. We optimized and developed a lipid glycation modelconsidering various reaction conditions (glucose concentration,temperature, buffer type, and pH) between PE and glucose. Usingthe developed model, various protein glycation inhibitors (aminoguanidine,pyridoxamine, and carnosine), antioxidants (ascorbic acid, ${alpha}$ -tocopherol,quercetin, and rutin), and other food compounds (L-lysine, L-cysteine,pyridoxine, pyridoxal, and pyridoxal 5'-phosphate) were evaluatedfor their antiglycative properties. Pyridoxal 5'-phosphate andpyridoxal (vitamin B₆ derivatives) were the most effective antiglycativecompounds. These pyridoxals could easily be condensed with PEbefore the glucose/PE reaction occurred. Because PE-pyridoxal5'-phosphate adduct was detectable in human red blood cellsand the increased plasma Amadori-PE concentration in streptozotocin-induceddiabetic rats was decreased by dietary supplementation of pyridoxal5'-phosphate, it is likely that pyridoxal 5'-phosphate actsas a lipid glycation inhibitor in vivo, which possibly contributesto diabetes prevention.

Supplementary key words lipid glycation inhibitor • phosphatidylethanolamine • diabetes

Abbreviations: AGE, advanced glycation end product; dioleoyl-PE, 1,2-di(cis-9-octadecenoyl)-sn-glycero-3-phosphoethanolamine; ELSD, evaporative light-scattering detection; LC, liquid chromatography; MRM, multiple reaction monitoring; MS, mass spectrometry; PCOOH, phosphatidylcholine hydroperoxide; PE, phosphatidylethanolamine; QTRAP LC/MS/MS, quadrupole/linear ion-trap liquid chromatography tandem mass spectrometry; RBC, red blood cell; STZ; streptozotocin

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