Joshi, Minakshi; (1991) Lipid peroxidation as an alternative pathway for bilirubin metabolism. Doctoral thesis (Ph.D), University of London, Royal Free Hospital School of Medicine.

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Abstract

A standard hepatic microsomal model for the peroxidation of membrane phospholipids was found to degrade bilirubin to colourless diazo-negative products. Lipid peroxidation (LPO) and bilirubin degradation (BRD) activities were strongly correlated and both showed identical requirements for cofactors and oxygen, regardless of whether peroxidation was initiated enzymatically or non- enzymatically. Bilirubin did not appear to have an antioxidant effect on LPO in the system tested. Superoxide anions, hydroxyl radicals and hydrogen peroxide were not found to have a significant role in microsomal BRD activity and are probably not the oxidants involved in the enzymatically driven, NADPH-dependent LPO studied. Lipid radicals arising during LPO are most likely the oxidising species involved in BRD. In order to examine the possible role of LPO in maintaining bilirubin homeostasis in the bilirubin UDP-glucuronyl transferase deficient Gunn rat, plasma bilirubin was modulated by altering the diet. A lipid free diet caused a significant rise in plasma bilirubin (BR), together with marked decreases in microsomal LPO and BRD activities, compared to a high lipid diet which resulted in a decrease in hyperbilirubinaemia and increased LPO and BRD activities. Neither of these diets influenced the microsomal ethoxyresorufin deethylase activity, suggesting that cytochrome P448 was not involved in the dietary effect. However, the high lipid diet resulted in a higher proportion of unsaturation in the fatty acid chains of the microsomal phpspholipid compared with normal or lipid free diets, which could account for the increased LPO. In vivo injection studies with two antioxidants were performed. Vitamin E, abolished LPO and BRD but did not alter plasma bilirubin concentration over 3 days. Vitamin C, had no effect on LPO and BRD and a variable effect on plasma bilirubin concentration. Both in vitro and dietary studies suggest that the oxidation of bilirubin by LPO might provide an alternative pathway for bilirubin disposal in Gunn rats.

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