Metabolism of 3-pentanone under inflammatory conditions

Abstract

Breath analysis of rats using multi-capillary column ion-mobility spectrometry (MCC-IMS) revealed alterations in acetone and other ketones, including 3-pentanone, during inflammation. The alterations seem likely to result from oxidative branched-chain keto acid (BCKA) catabolism. We therefore tested the hypothesis that 3-pentanone arises during inflammation from increased BCKA oxidation in the liver with consequent accumulation of propionyl-CoA and its condensation products. Male Sprague-Dawley rats were anaesthetised and ventilated for 24 h or until death. Exhaled breath was analysed by MCC-IMS while rats were injected with low and high doses of lipopolysaccharide (LPS), tumour necrosis factor α (TNFα), or vehicle. The exhaled 3-pentanone peak was identified by pure substance measurements. Blood was collected 12 h after treatment for the determination of cytokine concentrations; transcription enzymes for BCKA catabolism and the activity of the BCKA dehydrogenase were analysed in liver tissue by quantitative real-time PCR and western blotting. Exhaled 3-pentanone decreased in all groups, but minimum concentrations with high-dose LPS (0.24 ± 0.31 volts; mean ± SD), low-dose TNFα (0.17 ± 0.10 volts) and high-dose TNFα (0.13 ± 0.04 volts) were lower than in vehicle animals (0.27 ± 0.12 volts). At 60% and 85% survival times (svt) concentrations of exhaled 3-pentanone increased significantly in all animals treated with low-dose LPS, (svt 0.38 ± 0.18 volts, svt 0.62 ± 0.15 volts) and high-dose LPS (0.26 ± 0.28 volts, 0.40 ± 0.22 volts), as well as low-dose TNFα, (0.20 ± 0.09 volts, 0.39 ± 0.17 volts) and high-dose TNFα (0.18 ± 0.06 volts, 0.34 ± 0.08 volts), but not in vehicle rats (0.27 ± 0.12 volts, 0.30 ± 0.09 volts). BCKA catabolism was seen in the liver, with increased expression and activity of the branched-chain alpha-keto acid dehydrogenase (BCKD), lower expression of the propionyl-CoA carboxylase (PCC) subunits, and altered expression levels of BCKD regulating enzymes. Exhaled 3-pentanone may arise from altered BCKA catabolism. Our results suggest that excessive propionyl-CoA is possibly generated from BCKAs via increased activity of BCKD, but may undergo unusual condensation reactions rather than being physiologically processed to methylmalonyl-CoA by PCC. The pattern of 3-pentanone during early and prolonged inflammation suggests that reuse of BCKAs for the synthesis of new proteins might be initially favoured. As inflammatory conditions persist, substrates for cellular energy supply are required which activate irreversible degradation of excessive BCKA to propionyl-CoA yielding increased levels of exhaled 3-pentanone.

Volatilomic Signatures of AGS and SNU-1 Gastric Cancer Cell Lines

“…For example, 2-ethylhexanoic acid has been shown to be metabolized into 2-heptanone and 4-heptanone [23], and 2-pentanone is proposed to be formed via β-oxidation of hexanoic acid in the peroxisomal pathway [24]. Moreover, 3pentanone is also hypothesized to be produced via the oxidation of branched-chain keto acids [13]. More specifically, it is a product of the oxidative decarboxylation of 2-methyl-3-ketovaleric acid.…”

Nonhuman primate breath volatile organic compounds associate with developmental programming and cardio-metabolic status

“…Five of the VOCs detected, 2-pentanone, 2-octanone, 3,7-dimethyl-decane, 2,5,6-trimethyl-decane and 2,2,6-trimethyl-octane, have previously been reported in human breath samples [4, 6, 52, 53]; the fact that they are expressed differentially between males and females is likely due to different physiological states. Ketones and methylated hydrocarbons related to those reported in this study have been implicated in altered metabolic states [5, 6, 39, 44]. Although animals were on the same diet at the time of the breath collection, differences in nutrient utilization and social behaviors have the potential to impact metabolite output.…”

“…Quantifying VOCs yields signatures, which may indicate the metabolic state of the organism. VOCs, which are present in all bodily fluids [4], can be products of cellular metabolism [3, 5]. An intriguing aspect of VOC research is the potential to identify disease status by comparing samples from disease and non-disease states.…”

The Potential Antipyretic Mechanism of Gardeniae Fructus and Its Heat-Processed Products With Plasma Metabolomics Using Rats With Yeast-Induced Fever

“…L-valine belongs to the branched-chain amino acid (BCAA) family which plays an important role in brain function. Previous studies showed that the levels of BCAA metabolites were enhanced as inflammatory conditions persisted (Kleber et al, 2016). Moreover, the expression of IL-10 was increased in microglial cells in response to a high concentration of BCAA (De Simone et al, 2013).…”