The effect of chronic hypoxia on GSH-dependent detoxication in the small intestine

It is known that chronic O{dollar}sb2{dollar} deficiency impacts detoxication systems, but less is known about its effect on intestinal GSH-dependent detoxication. Thus, the objective of this dissertation is to characterize a normobaric chronic hypoxia model for study of GSH-dependent detoxication, and to determine the mechanisms of hypoxic exposure on metabolism and disposition of hydroperoxides in the small intestine. The first series of studies established the hypoxic steady state and evaluated the effect of prolonged O{dollar}sb2{dollar} deficiency on intestinal detoxication capacity. The results show that a clinically relevant hypoxia is achieved, as evidenced by decreased arterial O{dollar}sb2{dollar} saturation of hemoglobin, and elevated hematocrit and blood reticulocytes. A proximal-to-distal reduction in GSH redox enzymes suggests compromised intestinal detoxication capacity. Increased urinary thiobarbituric acid reactive substances is consistent with the presence of a generalized oxidative stress in hypoxic rats. The second series of studies assessed the effect of hypoxia on intestinal metabolism of hydroperoxides. The results showed that the initial rate of peroxide metabolism is accelerated in hypoxic enterocytes, but cellular integrity is impaired. Hypoxia results in a highly compromised thiol redox status, as well as loss of regulation of mitochondrial respiration. The third series of studies determined the impact of prolonged O{dollar}sb2{dollar} deficiency on lipid hydroperoxide absorption and disposition, and defined the contribution of glucose and reductant (GSH, NADPH) supply to intestinal peroxide detoxication. The results show that mucosal peroxide transport is increased in hypoxic compared to normoxic intestine. Determination of NADPH supply rate indicates that hypoxia decreases glucose availability for NADPH production, and thus exaggerates the thiol/disulfide imbalance.; Findings from these studies indicate that chronic hypoxia (1) imposes an oxidative stress on the small intestine and alters mucosal GSH-dependent enzymes, rendering the hypoxic intestine more vulnerable to oxidant injury; (2) imposes loss of metabolic regulation, resulting in a hyperdynamic state that predisposes the intestine to oxidant injury and metabolic failure; and (3) results in diversion of glucose from NADPH production which leaves little critical reserve to deal with additional oxidant challenges.