Cytochrome P450-endogenous substrates metabolism is reduced in patients with a multiple organ dysfunction after coronary artery bypass grafting

Abstract

Aim: To evaluate endogenous toxic substrates and liver monooxygenase function in cardiosurgical patients with multiple organ dysfunction syndrome (MODS). Methods: 45 patients with MODS and 34 patients with an uneventful postoperative period were studied. The endogenous substrates were quantified with blood middle molecules (MM). Liver monooxygenase function was evaluated with antipyrine (AP) pharmacokinetics. Results: On the first postoperative day, MODS patients were characterized by high concentration of toxic substrates (MM: +43.8%) and a significant decrease in liver monooxygenase function (AP clearance: −44%), while controls patients had a mild increase in endogenous substrates and a slight depression in monooxygenase function. On the 3rd–4th postoperative day, in the main group, endogenous substrates increased (MM: +53.1%), while in the control group toxic substrates decreased (MM: +6.9%). In both groups, an increase in liver monooxygenase function was noticed. Major differences were observed on the 10th–12th postoperative day. In the main group, toxic substrates remained elevated (MM: +37.5%) and monooxygenase function was depressed (AP clearance: −45.4%), while in the control group endogenous substrates and monooxygenase function were equal to the baseline. The correlation analysis showed a negative relationship between AP pharmacokinetics and endogenous substrates. Conclusion: Slowdown in liver microsomal oxidation is one of the main reasons for the accumulation of endogenous toxic substrates in MODS cardiac patients.

Transcriptomics, metabolomics, and in-silico drug predictions for liver damage in young and aged burn victims

“…Particularly distinctive was the downregulation of cytochrome P450 Cyp2 family genes involved in multiple liver functions, including protein and lipid metabolism, oxidative stress buffers, and metabolism of drugs and toxins 27 . These differences can result in a toxin metabolism shift in the liver cells and destabilization of free radical scavenging and DNA replication, recombination, and repair processes in aged animals after burn injury 28 , 29 .…”

“…Clinical evidence reveals that older patients have an attenuated inflammatory response to burn injury relative to younger injured subjects, followed by a hyper-inflammatory reaction 21 . Microsomal oxidation deceleration driven by cytochrome P450 was shown to play a critical role in developing MODS due partly to the accumulation of endogenous toxic compounds 27 . MODS was found to have increased incidence in the elderly after burn injury, but this was not accompanied by increased infection or sepsis rate 21 .…”

Transcriptomics, metabolomics, and in silico drug predictions to prevent or treat liver damage in young and aged burn victims

“…Particularly distinctive was the downregulation of cytochrome P450 Cyp2 family genes involved in multiple liver functions, including protein and lipid metabolism, oxidative stress buffers, and metabolism of drugs and toxins 41 . These differences can result in a toxin metabolism shift in the liver cells and destabilization of free radical scavenging and DNA replication, recombination, and repair processes in aged animals after burn injury 42,43 .…”

“…Clinical evidence reveals that older patients have an attenuated in ammatory response to burn injury relative to younger injured subjects, followed by a hyper-in ammatory reaction 35 . Microsomal oxidation deceleration driven by cytochrome P450 was shown to play a critical role in developing multi-organ dysfunction syndrome (MODS) due partly to the accumulation of endogenous toxic compounds 41 .…”