Metabolic Profiles Of Ketolysis And Glycolysis In Malignant Gliomas: Possible Predictors Of Response To Ketogenic Diet Therapy.
e13048 Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human brain tumors may also be sensitive to ERKD, we used immunohistochemistry reactions on formalin fixed paraffin embedded tumor samples to evaluate for the presence of enzymes important for the metabolism of ketones and glucose. Methods: Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: low positive<5% (LOW); intermediate (INT) 5-20%; and highly positive (HIGH) >20%. Focal non-neoplastic “normal” brain tissue present within the specimens served as positive internal controls. Results: Succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) are mitochondrial enzymes important for metabolizing beta hydroxy butyrate, the main ketone in blood. Both of these enzymes were either decreased or absent (INT or LOW) concordantly in 14 of the 17 (82%) GBMs, an Continue reading >>
Chapter 152. Disorders Of Ketolysis
Ketolysis involves esterification of acetylacetonate (AcAc) to AcAcCoA by succinyl-CoA: 3-oxoacid transferase (SCOT) and involves hydrolysis of AcAcCoA by 3-ketothiolase to form acetyl-CoA.1 SCOT deficiency is characterized by episodic ketoacidosis, often beginning in infancy, with increased blood ketone bodies even in the fed state. Diagnosis can be established by enzyme assay in fibroblasts or by mutation analysis, and prenatal diagnosis can be accomplished in the same manner. Mitochondrial 3-ketothiolase releases acetyl-CoA from acetoacetyl-CoA and from 2-methylacetoacetyl-CoA, an intermediate in isoleucine oxidation (see Chapter 156). Enzyme deficiency can present in infancy with hyperammonemia, metabolic acidosis, and severe ketosis, or later with fasting- or protein-induced episodes of vomiting, hepatomegaly, ketoacidosis, and encephalopathy. Urine organic acid analysis shows increased 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine, but they may be obscured during acute illnesses by 3-hydroxybutyrate (3HB) and acetoacetate (AcAc) and may be detectable only between episodes or after an oral load of isoleucine. Glycine levels are often elevated in b Continue reading >>
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