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List of Metabolites and Patterns of Metabolites for Compound B

The metabolites, which significantly changed for the animals dosed with compound B, were identified by the PCA shown before and by using spectrum databases of metabolites. When inspecting the table of most significantly changed metabolites, it is obvious that several metabolites can be combined to patterns with biochemical interpretations. The metabolic meaning of the changes can be briefly summarized as follows:

  • Simultaneous increases of Creatine and Taurine levels in urine are a typical sign of hepatocyte necrosis

  • On the one hand the occurence of Betaine in human urine has been associated with an impairment of the kidney, which usually reabsorbs betaine oxidized from choline. On the other hand, inceases of Betaine in the urine have been observed for two liver toxins within the database of 142 animal studies compiled during the COMET project. Although a reliable interpretation of the presence of Betaine is lacking at the moment, a leakage of Betaine (the oxidized form of the important metabolite choline) is a sign of a significant impairment of biology.

  • The simultaneous increase of Glucose and decrease of Creatinine is a sign of tubular nephrotoxicity.

  • Changes of the pattern of concentration levels of Hippurate, 3-Hydroxyphenylpropionate, Hydroxycinnamate and Phenylacetylglycine are associated with the gut microflora.

  • The metabolites are Citrate, 2-Oxoglutarate, Malate, Succinate, Fumarate and Isocitrate are all citrate cycle intermediates. A down-regulation of the citrate cycle can be a sign of mitochondrial impairments on the one side. On the other side, a down-regulation of citrate cycle intermediates is often observed for toxic side effects of drugs and consequently can also be a sign of animals not feeling well. These two effects can be differentiated by exact quantifications of the concentration levels of the metabolites, as both effects affect different intermediates of the citrate cycle to a different extend.

  • Trigonelline is an unspecific metabolite and is often down-regulated for animals not feeling well.

  • In addition a new metabolite was identified, which can be associated with changes of the steroid synthesis (see later..)

Creatine + + Specific pattern for hepatocyte necrosis
Taurine + +
Betaine + + Marker for liver and kidney toxicity
Glucose
+ +
Specific pattern for tubular nephrotoxicity
Creatinine
- -
Hippurate
-
Pattern of metabolites specific for changes of the gut microflora
3-HPPA
-
HCA
-
PAG
-
Citrate
-
Intermediates of citrate cycle:
  • Mitochondrial effects
  • Impaired wellness
2-Oxoglutarate
-
Malate
-
Succinate
-
Fumarate
-
Isocitrate
-
Trigonelline
-
Impaired wellness
New Metabolite
+ +
Steroid synthesis, see later...
Metabolites, which are most significantly up- and down-regulated for animals dosed with compound B. In addition, the extend of change and the biochemical interpretation of the markers and of the patterns of markers are shown.

 

 

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