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The Effects of Diet on Drug Metabolism in the Rat.

Hauton, David. (1995) The Effects of Diet on Drug Metabolism in the Rat. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Feeding of modified diets to Wistar rats modulated various drug-metabolising enzymes including the cytochrome P450 monooxygenases, the Phase II conjugation enzymes and the enzymes providing protection from oxidative damage. Replacement of dietary carbohydrate derived from starch with glucose or fructose were largely without effect towards the cytochromes P450 monooxygenases or the Phase II conjugation enzymes. However, diets high in sucrose decreased lauric acid hydroxylase activity and modestly decreased cytosolic catalase. Administration of vitamin E - deficient diets for seven weeks decreased hepatic pentoxyresorufin - O - dealkylase and increased erythromycin N -demethylase, however, CYP3A apoprotein levels were not influenced by this treatment. Intermittent dietary restriction was observed to retard the growth of rats. In addition, periods of calorie restriction were found to decrease serum concentrations of triglycerides and cholesterol. Changes to hepatic microsomal suspensions were also recorded, including increases in the activities of methoxy- and pentoxy - resorufin - O - dealkylase and in total cytochrome P450 concentrations. Upon subsequent refeeding, these changes returned to control levels within 24 hours. Repeated cycles of food restriction and refeeding had no effect on hepatic cytochromes P450. Food restriction also decreased hepatic glutathione concentrations and induced a compensatory increase in hepatic glutathione reductase activity. Oral intubation of increasing concentrations of sodium/copper chlorophyllin had no effect on cytochrome P450 monooxygenases and produced only modest increases in the activity of glutathione - S - transferase, at the lowest dose of chlorophyllin administered. The potent antimutagenic properties of chlorophyllin in the Ames test were confirmed during these studies. Modification of dietary methionine levels, whether deficiency or supplementation, could modulate the activities of hepatic cytochromes P450. Dietary supplementation with methionine induced CYP2E1 activity, as exemplified by p - nitrophenol hydroxylase. Dietary methionine deficiency decreased the liver weight and, in 'the presence of the procarcinogen benzo[a]pyrene, caused a profound hypertrophy of the liver. In addition, induction of CYP1A2 by benzo[a]pyrene was potentiated by methionine deficiency. Moreover, methionine deficiency decreased hepatic glutathione concentrations by ~80% and caused a compensatory increase in hepatic glutathione reductase activity. Dietary methionine deficiency enhanced the expression of hepatic c - myc oncogene products as recorded by immunoblot analysis. Investigation of dietary methionine deficiency upon renal and pulmonary tissue revealed that deficiency decreased lauric acid hydroxylase activity in the kidney. When methionine deficient animals were treated with benzo[a]pyrene, a profound induction of renal microsomal lauric acid hydroxylase activity was recorded. In addition, the combined treatments of methionine deficiency and benzo[a]pyrene administration also decreased pulmonary glutathione reductase activity compared to benzo[a]pyrene -pretreated rats receiving a control diet. These observations suggest that methionine deficiency may have limited effects upon pulmonary and renal tissues, the greatest impact being observed in the liver. Critical appraisal of the efficacy of dietary antimutagens and anticarcinogens has revealed that many classes of such anutrients, whilst demonstrating potent anti - cancer properties in rodent bioassays, may be of limited efficacy for human subjects as insufficient quantities of these anutrient species are consumed in the diet or absorbed from the GI tract.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Hauton, David.
Date : 1995
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1995.
Depositing User : EPrints Services
Date Deposited : 24 Apr 2020 15:27
Last Modified : 24 Apr 2020 15:27
URI: http://epubs.surrey.ac.uk/id/eprint/855368

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