Histidine-induced injury to cultured liver cells, effects of histidine derivatives and of iron chelators

Abstract

The amino acid histidine is an excellent buffer and is therefore included in several organ preservation solutions used in transplantation medicine. However, when used at concentrations as in these solutions, histidine has a marked injurious potential. Therefore, we here assessed the mechanism of histidine-induced cell injury and searched for ways to use the buffering power of histidine but avoid histidine toxicity. When cultured hepatocytes were incubated in HTK solution or in modified Krebs-Henseleit buffer containing 198 mM L-histidine at 37 degrees C, most cells lost viability within 3 h (LDH release 86 +/- 7% and 89 +/- 5%, respectively). This injury was accompanied by marked lipid peroxidation, and was strongly inhibited by hypoxia, by the antioxidants trolox, butylated hydroxytoluene and N-acetylcysteine and by the membrane-permeable iron chelators 2,2'-dipyridyl, 1,10-phenanthroline, LK 614, LK 616 and deferoxamine. Thus, histidine-induced cell injury appears to be mediated by an iron-dependent formation of reactive oxygen species. D-Histidine, imidazol and L-histidine methyl ester also elicited marked injury, while the N-substituted derivatives Nalpha-acetyl-L-histidine and tert-butyl-oxycarbonylhistidine and histidine-containing dipeptides showed almost no toxicity. Histidine toxicity, its iron dependence and the superiority of Nalpha-acetyl-L-histidine were also evident during/after cold (4 degrees C) incubations. Therefore, we suggest the addition of iron chelators to histidine-containing solutions, and/or replacing histidine with Nalpha-acetyl-L-histidine in organ preservation solutions.

Effect of histidine on autotaxin activity in experimentally induced liver fibrosis

“…Rauen et al [39] stated that histidine toxicity is mediated by an iron-dependent pathway. Histidine can chelate Fe 2+ ions and also can form adduct with H 2 O 2 .…”

Polypharmacy, multiple natural health products and hepatotoxicity

“…Several of the natural health products have been associated with hepatotoxicity; however, much of the information about these associations is from studies done on animals or in vitro, and precise dosage information is limited. [4][5][6][7][8][9][10][11][12]15 Both venlafaxine and varenicline have been reported to cause hepatotoxicity in patients, especially in those with underlying liver conditions. [1][2][3] Tables 1 and 2 provide summaries of the patient's medications and any published evidence of hepatotoxicity associated with their use.…”

“…Over the past three months, she had been taking six prescription medications (Table 1) 1-3 and seven natural health products (Table 2). [4][5][6][7][8][9][10][11][12] Her bilirubin level had been elevated (281 [normal 3.4-22] µmol/L), as had her liver enzyme levels (alanine transaminase 755 [normal ] U/L and alkaline phosphatase 273 [normal 42-98] U/L). An ultrasound of her abdomen had been consistent with cirrhosis, and the presumptive diagnosis had been cirrhotic liver disease.…”

Evaluation of Functional and Structural Alterations in Muscle Tissue after Short-Term Cold Storage in a New Tissue Preservation Solution

“…Current preservation methods (0.9% NaCl-moistened gauze) and solutions (HTK and UW) do not consider this mechanism as they originally do not contain iron chelators. TiProtec and the variants used in this study contain N -acetylhistidine as buffer because histidine, the main buffer system of the HTK preservation solution, and phosphate, the main buffer system of the UW solution, are excellent buffers but also exert some toxicity [Rauen et al, 2007]. Nacetylhistidine does not share this toxicity [Rauen et al, 2007].…”

“…TiProtec and the variants used in this study contain N -acetylhistidine as buffer because histidine, the main buffer system of the HTK preservation solution, and phosphate, the main buffer system of the UW solution, are excellent buffers but also exert some toxicity [Rauen et al, 2007]. Nacetylhistidine does not share this toxicity [Rauen et al, 2007]. TiProtec and its variants contain glycine and alanine to avoid the formation of non-specific pores resulting in sodium influx into the cells, a major mechanism of hypoxic injury [Carini et al, 1997;Frank et al, 2000;Rauen and de Groot, 2004].…”