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v, 88 leaves : graphs, photos ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1980

Thesis (Ph.D.) -- University of Adelaide, Department of Biochemistry, 1980.

The influence of peripubertal exposure to physiological levels of testosterone on the adult androgen responsiveness of the cytochrome P450 enzyme activity, hepatic microsomal erythromycin demethylase activity, was investigated. Rats were injected subcutaneously with testosterone enanthate 5 µmoles/kg/day either peripubertally, during adulthood or in both time periods. In adult untreated rats, hepatic microsomal erythromycin demethylase activity was higher in males than in females. Intact adult male rats, but not intact adult female rats, responded to adult testosterone treatment with an increase in hepatic microsomal erythromycin demethylase activity. Female and male rats were gonadectomized before the onset of puberty. In the adult female rats which had been prepubertally ovariectomized, exposure to testosterone peripubertally resulted in an adult androgen responsiveness for hepatic microsomal erythromycin demethylase activity. This indicated that the potential is present in the prepubertally ovariectomized female rat for the pubertal imprinting by testosterone of an adult androgen responsiveness for hepatic microsomal erythromycin demethylase activity. Prepubertal castration of male rats reduced hepatic microsomal erythromycin demethylase activity and plasma testosterone levels from control levels. Hepatic microsomal erythromycin demethylase activity was found to be partially correlated with plasma testosterone levels. The higher hepatic microsomal erythromycin demethylase activity in the adult male rat may therefore be related to high adult male levels of circulating testosterone. The administration of testosterone to adult male rats which had been prepubertally castrated resulted in hepatic microsomal erythromycin demethylase activity which was lower than that of intact males and of intact males treated with testosterone in adulthood. These results indicated that adult androgen responsiveness of hepatic microsomal erythromycin demethylase activity is not completely imprinted in male rats in the neonatal period. This study provided evidence in support of the hypothesis that the peripubertal period is a time during which imprinting by testosterone of adult androgen responsiveness of hepatic P450 enzymes can occur. / Pharmaceutical Sciences, Faculty of / Graduate

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It has been suggested that membrane characteristics associated with carcinomas could be related to an altered molecular structure of lipids inplasma membrane. The microsomal and soluble fractions of the cell are major sites of de novo synthesis and elongation/desaturation of fatty acids. It was the purpose of this study to compare the fatty acid composition of microsomal and soluble fractions isolated from mammary adenocarcinomas with that of normal mammary tissue and to determine if deviations found in the plasma membrane isolated from tumors could be observed at these subcellular levels.Microsomal and soluble fractions were isolated by differential centrifugation from mammary adenocarcinomas and from normal mammary tissue of Strain A female mice. Activities of nicotinamide adenine dinucleotide, reduced (NADH) dependent cytochrome c reductase andnicotinamide adenine dinucleotide phosphate, reduced (NADPH) dependent cytochrome c reductase in these fractions were determined. The fatty acids were extracted, methylated, and methyl esters identified and quantified using gas liquid chromatography. Polar and non-polar GLC columns, silver nitrate thin layer chromatography, hydrogenation, and spiking was used to confirm the identity of some fatty acids.Fatty acid composition of the microsomal and soluble fractions was similar in tumor and normal tissue. There was a greater percentage of C24:1 in tumors. A reversal of the oleic to stearic acid ratio, an increase in the level of palmitic acid, and a tendency toward long chain polyenoic fatty acids, as reported in studies on the plasma membrane isolated from tumors, was not evident in either the microsomal or soluble fractions. There was evidence of greater utilization of NADPH in the reduction of cytochrome c reductase in tumors. This may result in a decreased availability of NADPH for fatty acid synthetase and lipogenesis.Results of this study do not demonstrate support for a shift in the biosynthetic pathway for the synthesis of fatty acids in carcinomas. It is possible that changes in the lipid composition in the plasma membrane of tumor cells occur after initial incorporation or a shift in biosynthesis could occur in the mitochondria, another site of de novo synthesis and elongation/desaturation of fatty acids.

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