Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

Abstract

Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.

Polymer‐Assisted Co‐Assembly towards Synthesis of Mesoporous Titania Encapsulated Monodisperse PdAu for Highly Selective Hydrogenation of Phenylacetylene

“…This is indicative of effective nanoconfinement provided by colloidal templates to avoid the sintering of PdAu under high temperature treatment. [25] The atomic ratio of Pd to Au estimated from energy dispersive X-ray spectroscopy (EDS) is 49 : 51 similar to the feeding ratio during synthesis (Table S1). Homogeneously alloying after high temperature calcination without phase separation is clearly observed from the EDS mapping ( Figure 1e).…”

Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research

“…Intraperitoneal (i.p.) administration of excessive doses of certain amino acids, such as L-arginine (Toma et al, 2000 ), L-ornithine (Rakonczay et al, 2008 ), L-lysine (Biczo et al, 2011b ), and L-histidine (Zhang et al, 2018 ), causes necrotising AP in rats and/or mice. Why these particular basic amino acids induce AP has not yet been fully clarified, but is likely related to shared metabolic pathways in vivo determined by the structural similarities.…”

“…The mechanisms of AP induced by L-arginine remain unclear. Amino acid imbalance (Mizunuma et al, 1984 ), reactive oxygen species (Czako et al, 1998 ; Rakonczay et al, 2003 ), inflammatory mediators (Czako et al, 2000 ; Takacs et al, 2002b ; Rakonczay et al, 2003 ), nitric oxide (Takacs et al, 2002a ), cytoskeletal changes (Tashiro et al, 2001 ), intracellular Ca 2+ signaling (Zhang et al, 2018 ), mitochondrial dysfunction (Biczo et al, 2018 ; Zhang et al, 2018 ) and endoplasmic reticulum stress (Kubisch et al, 2006 ) have all been postulated to be involved in this process.…”

“…Biczo et al found that pancreatic polyamine catabolism was activated in L-ornithine-induced AP, and tried to ameliorate it with metabolically stable polyamine analogs, which turned out ineffective (Biczo et al, 2010 ). We also tried to induce AP with L-ornithine (2 × 4 g/kg) in mice, but found the model to be excessively severe and mice were dead within few hours (Zhang et al, 2018 ).…”

“…injection of 3 g/kg L-histidine had no effect on the rat pancreas (Biczo et al, 2011a ), our group reported for the first time that i.p. administration of 2 × 4 g/kg L-histidine (1 h apart) to mice can induce AP (Zhang et al, 2018 ). L-histidine at a dose of >3 g/kg could also likely trigger AP in rats, but this has not yet been tested.…”