Background & Aims: Butyrate oxidation by colonocytes is impaired in ulcerative colitis (UC). This study examined the activity of enzymes involved in butyrate oxidation in UC.
Methods: Activities of mitochondrial acetoacetyl CoA thiolase, crotonase and β-hydroxy butyryl CoA dehydrogenase were estimated spectrophotometrically in rectosigmoid mucosal biopsies from patients with UC, Crohn's colitis, and control subjects undergoing colonoscopy for colon cancer or rectal bleeding.
Results: Activity of mitochondrial acetoacetyl CoA thiolase was decreased by 80% in UC (3.4 ± 0.58 μmol/min/g wet wt, n=30) compared to control (16.9 ± 3.5, n=18) and to Crohn's colitis (17.6 ± 3.1, n=12) (P<0.0001). The activity of two other mitochondrial butyrate oxidation enzymes - crotonase and β-hydroxy butyryl CoA-dehydrogenase - as well as of cytoplasmic thiolase was normal in UC. Mitochondrial thiolase activity in UC did not correlate with clinical, endoscopic or histological indices of disease severity. Mitochondrial thiolase activity was reduced in the normal right colon mucosa of patients with left-sided ulcerative colitis. Enzyme kinetic studies revealed lowered Vmax, suggesting inhibition at a site distinct from the catalytic site. Reduced thiolase activity in UC was returned to normal by exposure to 0.3mM β-mercaptoethanol, a reductant. Using normal colon mucosal biopsies redox modulation of thiolase activity by hydrogen peroxide, a mitochondrial oxidant, could be shown. A significant increase in hydrogen peroxide formation was observed in UC biopsies.
Conclusion: A defect of mitochondrial acetoacetyl CoA thiolase occurs in UC. Increased reactive oxygen species generation in mitochondria of epithelial cells in UC may underlie this defect.
- butyrate oxidation
- mitochondrial thiolase
- ulcerative colitis
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