Ascorbic acid deficiency and liver disease: Effects on ethanol oxidizing enzymes

Dow, James (1975) Ascorbic acid deficiency and liver disease: Effects on ethanol oxidizing enzymes. PhD thesis, University of Glasgow.

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Abstract

1.(a) A significant decrease in the extent of the redox state shift after ethanol administration was obtained in chronic ethanol treated normal and ascorbic acid deficient guinea pigs, compared with their respective controls. (b) This was not due to differences in blood ethanol concentration between acute and chronic ethanol treated animals, as the theoretical zero time blood ethanol concentration was the same in all the groups of animals. (c) The decrease in the redox state shift after chronic ethanol administration may represent metabolic adaptation to ethanol at the mitochondrial level. As this was achieved after a relatively short period of exposure to ethanol, it is likely that it can occur in man after exposure to comparable quantities of ethanol. (d) Although the redox state is important in the regulation of ethanol elimination in vivo, the approximately 10 per cent decrease in its shift, after ethanol administration to chronic ethanol treated animals, had no effect on their rate of ethanol elimination, (e) There was no statistica.1 difference between the redox states of ascorbic acid deficient groups and their corresponding normal controls. 2.(a) Microsomal protein content and aniline hydroxylase and KADFH oxidase activities, were significantly reduced in ascorbic acid deficient guinea pigs, although catalase and MEOS activities were unchanged. Cytochrome P-450 content was also significantly decreased, but no change was observed in cytochrome b5 content. (b) Although the half life of diphenylhydantoin was increased by 36 per cent in the ascorbic acid deficient guinea pig, no change in the rate of ethanol clearance from the blood was found. (c) Chronic ethanol treatment did not induce microsocial enzyme activities or increase cytochrome P-450 content. (d) Phenobarbitone pretreatment of guinea pigs resulted in increases in liver/body wt, activity of aniline hydroxylase, cytochrome P-450 content and microsomal protein, although this had no effect on the rate of ethanol clearance from the blood. (e) As MEOS activity was not dependent on cytochrome P-450 content, and did not parallel changes in the activity of aniline hydroxylase, it does not have properties associated with established microsomal drug metabolizing enzymes. 3.(a) A significant correlation coefficient (r = 0.88, P<0.001) was obtained when hepatic alcohol dehydrogenase activities of 12 patients with non-alcoholic liver disease were plotted against their corresponding leucocyte ascorbic acid content. (b) The rate of clearance of ethanol from the blood of 11 healthy male volunteers was significantly increased after oral ascorbic acid supplementation. (c) Hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content were measured in 55 patients with liver disease and in 10 control subjects with duodenal ulcer. The patients with liver disease were divided into non drinkers, moderate drinkers and alcoholic/heavy drinkers. (d) There was no significant difference in hepatic alcohol dehydrogenase activity between the groups with liver disease, but they had less than half the hepatic alcohol dehydrogenase activity of the control subjects. (e) A correlation coefficient of r = 0.77 (P<0.001) was obtained when the hepatic alcohol dehydrogenase activity of each patient with liver disease v/as plotted against its corresponding leucocyte ascorbic acid content. An insignificant correlation coefficient r = 0.352 was found in the control subjects, who had no evidence of liver disease. (f) when this was repeated with the liver disease patients divided according to their previous alcohol intake, significant correlation coefficients of r = 0.873 (P<0.001) for the non drinkers, r = 0.739 (F<0.02) for the moderate drinkers, and r = 0.702 (p<0.005) for the alcoholic/heavy drinkers were obtained. (g) The addition of ascorbic acid in vitro (0.5 mM to 10 mM) had no effect on the activity of alcohol dehydrogenase. (h) The relation between hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content is probably a consequence of liver disease, as opposed to any specific effect of ascorbic acid status on alcohol dehydrogenase activity. 4. (a) A 4% incidence of the atypical form of human alcohol dehydrogenase was found in a Scottish population. This exhibited a bimodal distribution. 5. (a) The activity of the NADPH dependent ethanol oxidizing system v/as increased in patients with liver disease. This was significant whether activities were expressed per mg protein or per g wet wt liver. (b) It is suggested that the NADPH dependent ethanol oxidizing system maintains normal rates of ethanol metabolism in patients with liver disease. The greater activity of the NADPH dependent system in patients with liver disease may compensate for the low/ alcohol dehydrogenase activities found in these patients.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: A Goldberg
Keywords: Medicine, Toxicology
Date of Award: 1975
Depositing User: Enlighten Team
Unique ID: glathesis:1975-74249
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33
URI: http://theses.gla.ac.uk/id/eprint/74249

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