Wew. Roediger et al., SULFIDE IMPAIRMENT OF SUBSTRATE OXIDATION IN RAT COLONOCYTES - A BIOCHEMICAL BASIS FOR ULCERATIVE-COLITIS, Clinical science, 85(5), 1993, pp. 623-627
1. Isolated colonic epithelial cells of the rat were incubated for 40m
in with [6-C-14]glucose and n-[1-C-14]butyrate in the presence of 0.1-
2.0 mmol/l NaHS, a concentration range found in the human colon. Metab
olic products, (CO2)-C-14 acetoacetate, beta-hydroxybutyrate and lacta
te, were measured and injury to cells was judged by diminished product
ion 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 rem
ained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxida
tion were dose-dependently reduced at the same rate. 3. To bypass shor
t-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidati
on, ketogenesis from crotonate was measured in the presence of 1.0 mmo
l/l NaHS. Suppression by sulphide of keto-genesis from crotonate (-10.
5+/-6.1%) compared with control conditions was not significant, wherea
s suppression of ketogenesis from n-butyrate (-36.00+/-5.14%) was sign
ificant (P = < 0.01). Inhibition of FAD-linked oxidation was more affe
cted 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, suggesti
ng a global reversal of the action of sulphide. 5. Sulphide-induced ox
idative changes closely mirror the impairment of beta-oxidation observ
ed in colonocytes of patients with ulcerative colitis. A hypothesis fo
r the disease process of ulcerative colitis is that sulphides may form
persulphides with butyryl-CoA, which would inhibit cellular short-cha
in acyl-CoA dehydrogenase and beta-oxidation to induce an energy-defic
iency state in colonocytes and mucosal inflammation.