Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis?
1. Isolated colonic epithelial cells of the rat were incubated for 40 min with [6-14C]glucose and n-[1-14C]butyrate in the presence of 0.1-2.0 mmol/l NaHS, a concentration range found in the human colon. Metabolic products, 14CO2, acetoacetate, beta-hydroxybutyrate and lactate, were measured and injury to cells was judged by diminished production of metabolites. 2. Oxidation of n-butyrate to CO2 and acetoacetate was reduced at 0.1 and 0.5 mmol/l NaHS, whereas glucose oxidation remained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxidation were dose-dependently reduced at the same rate. 3. To bypass short-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidation, ketogenesis from crotonate was measured in the presence of 1.0 mmol/l NaHS. Suppression by sulphide of ketogenesis from crotonate (-10.5 +/- 6.1%) compared with control conditions was not significant, whereas suppression of ketogenesis from n-butyrate (-36.00 +/- 5.14%) was significant (P = < 0.01). Inhibition of FAD-linked oxidation was more affected by NaHS than was NAD-linked oxidation. 4. L-Methionine (5.0 mmol/l) significantly redressed the impaired beta-oxidation induced by NaHS. Methionine equally improved CO2 and ketone body production, suggesting a global reversal of the action of sulphide. 5. Sulphide-induced oxidative changes closely mirror the impairment of beta-oxidation observed in colonocytes of patients with ulcerative colitis. A hypothesis for the disease process of ulcerative colitis is that sulphides may form persulphides with butyryl-CoA, which would inhibit cellular short-chain acyl-CoA deHydrogenase and beta-oxidation to induce an energy-deficiency state in colonocytes and mucosal inflammation.
Roediger
W E
WE
University of Adelaide, Department of Surgery, Queen Elizabeth Hospital, Adelaide, Australia.
Duncan
A
A
Kapaniris
O
O
Millard
S
S
D000818:Animals; D002087:Butyrates / Q000378:metabolism; D020148:Butyric Acid; D002245:Carbon Dioxide / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013440:Sulfides / Q000378:metabolism*
D002087:Butyrates; D007657:Ketone Bodies; D013440:Sulfides; D020148:Butyric Acid; D002245:Carbon Dioxide; D008715:Methionine; C025451:sodium bisulfide; D005947:Glucose