Methionine metabolism in an animal model of sepsis

Abstract

Background: Sepsis is a disease with high incidence and lethality and is accompanied by profound metabolic disturbances. In mammalian methionine metabolism, S-adenosylmethionine (SAM) is produced, which is important in the synthesis of neurotransmitters and glutathione and as an anti-inflammatory agent. The degradation product and antagonist of SAM is S-adenosylhomocysteine (SAH). In this study, we investigated changes in methionine metabolism in a rodent model of sepsis. Methods: Sepsis was induced in male Wistar rats (ns21) by intraperitoneal injection of bacterial lipopolysaccharide (10 mg/kg). Controls (ns18) received vehicle only. Blood was collected by cardiac puncture 24 h later. Puncture of the suboccipital fossa was performed to collect cerebrospinal fluid (CSF). Methionine metabolites were measured using stable isotope dilution tandem mass spectrometry. Plasma total homocysteine and cysteine were measured by HPLC using fluorescence detection. Glutathione was assayed using a modified enzymatic microtiter plate assay. Results: We observed significantly higher plasma levels of SAM (p-0.001) and SAM/SAH ratio (ps0.004) in septic animals. In CSF, there was also a trend for higher levels of SAM in septic animals (ps0.067). Oxidative stress was reflected by an increase in the ratio of oxidized/reduced glutathione in septic animals (ps0.001). Conclusions: Sepsis is associated with an increase in SAM/SAH ratio in plasma and CSF in rodents. This indicates an altered methylation potential during sepsis, which may be relevant for sepsis-associated

Methionine Metabolites in Patients With Sepsis

“…High SAM levels have previously been observed after experimental lipopolysaccharide challenge in rats. 5 Finally, we found that elevated SAM and SAH levels in nonsurvivors versus survivors can be accounted for by more severe renal impairment in the nonsurvivors. The important effect of renal function is further supported by the observation that declining SAM and SAH levels over time are accompanied by declining creatinine concentrations (in survivors), and persistent elevations in SAM and SAH levels are accompanied by persistent renal dysfunction (in nonsurvivors; Table 5).…”

“…Dysregulated methionine metabolism has been implicated in cardiovascular disease 3,4 and sepsis. [5][6][7][8] Methionine is enzymatically converted to S-adenosylmethionine (SAM), the major substrate for transmethylation reactions 9 and initial precursor for homocysteine and glutathione production (Figure 1). S-adenosylhomocysteine (SAH) is the by-product of SAM transmethylation reactions, is in equilibrium with homocysteine, and provides negative feedback regulation on methyltransferase activity.…”

Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study

“…These metabolites may offer a more relevant, amplified signature in sepsis and can be measured using techniques such as 1 H nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS) [9]. To date, the application of metabolomic (or metabonomic) profiling in sepsis is limited to animal studies [10–13], or to specific metabolic pathways, such as tryptophan/kynurenine [14], arachidonic acid [15], or arginine metabolism [16], among others [17]. One study found using 1 H-NMR found differences in glutathione, adenosine, sphingomyelin, and phosphatidylserine between healthy controls and ventilated patients with sepsis-associated acute lung injury [18].…”

Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis

“…[8][9][10] A major source of cysteine is transsulfuration from homocysteine (Hcy), a pathway which is also affected in sepsis. 11,12 A recent study focusing on the plasma metabolome in septic patients revealed correlation of alpha-n-aminobutyric acid with the patients Sequential Organ Failure Assessment (SOFA) Score and cystathionine levels. 13 Both cystathionine and alpha-n-aminobutyric acid are metabolites of Hcy downstream of the cystathionine betasynthase (CBS, EC 4.2.1.22) reaction.…”