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Title: Studies in the biogenesis of steroid hormones
Author: Cameron, Euan H. D.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1966
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The purpose of the investigation was to determine whether the histochemically defined picture of 3beta-hydroxysteroid dehydrogenase distribution in the adrenal cortex of horse and man could be confirmed biochemically. Attempts were also made to investigate the significance of this distribution. PART I. Histochemistry has shown that the highest 3beta-hydroxysteroid dehydrogenase activity is in the outer zona fasciculate with little or no activity is in the outer zona fasciculate with little or no activity in the zona reticularis. This result is obtained with substrates dehydrocpiandrosterone, pregnenolone and 17alpha-hydroxypregnenolone. Evidence is now presented that DNA and pregnenolone-3beta-hydroxy dehydrogenase activity (and possibly 17alpha-hydroxy-pregnenolone-3beta-hydroxy dehydrogenase activity) is higher in the zona fasciculate of the adrenal cortices of horse and man. The results obtained, however, do not indicate the large difference in activity suggested by the histochemical evidence, and indeed it was found that reticular tissue contains substantial amounts of 3beta-hydroxysteroid dehydrogenase activity. PART II. The ability of fascicular and reticular cells of the horse adrenal cortex to transform [7a-3H] pregnenolone, [4-14C] progesterone, [7a-3H] 17alpha-hydroxypregnenolone, and [4-14C] 17alpha-hydroxyprogesterone to cortisol was measured. It was found that:- 1. All four steroids are transformed to cortisol by both types of cell. 2. The transformation of all four steroids to cortisol is higher in fasciular tissue. 3. The sequences pregnenolone → 17alpha-hydroxypregnolone → 17alpha-hydroxyprogesterone and pregnenolone → progesterone → 17alpha-hydroxyprogesterone are both slower than the succeeding steps from 17alpha-hydroxyprogesterone → cortisol. 4. The step 17alpha-hydroxypregnenolone → 17alpha-hydroxyprogesterone is rate-limiting in the transformation of 17alpha-hydroxypregnenolone → cortisol and there is approximately 2.4 times more 17alpha-hydroxypregnenolone-3B-hydroxy dehydrogenase activity in fascicular than in reticular tissue. 5. Progesterone-17alpha-hydroxylase activity is between 1.67 and 2.91 times higher in fascicular than in reticular tissue. Following the experiments with horse adrenal cells, an attempt was made with human adrenal tissue to investigate the alternative metabolic pathways which convertpregnenolone to 17alpha-hydroxyprogesterone with a view to the elucidation of the role of 3B-hydroxysteroid dehydrogenase. [7a-3H] pregnenolone and [4-14C] progesterone were incubated simultaneously with fascicular and with reticular slices from a normal human adrenal cortex. Conversions of each substrate to 16a-hydroxyprogesterone, 11-deoxycorticosterone, 17alpha-hydroxyprogesterone and cortisol were measured. Evidence was found suggesting that:- 1. Both fascicular and reticular tissue convert pregnenolone and progesterone to the four metabolites mentioned above. 2. Pregnenolone is converted to these metabolites in greater yield in fascicular tissue compared with reticular tissue. 3. The conversion of progesterone to these metabolites is only marginally greater in fascular tissue. 4. Pregnenolone → progesterone → 11-deoxycorticosterone is the only major pathway for the formation of 11-deoxycorticosterone in both zones. 5. The main route from pregnenolone to 16a-hydroxyprogesterone is via 16a-hydroxypregnenolone in both zones. 6. The pathway pregnenolone → 17alpha-hydroxypregnenolone → 17alpha-hydroxyprogesterone → 11-deoxycortisol → cortisol is the major route to cortisol from pregnenolone in vitro in the adrenal cortex and the preference for this pathway is greater in fascicular tissue. 7. It is possible that a pathway exists from 17alpha→hydroxypregnenolone to cortisol in fascicular tissue independent of 17alpha→hydroxyprogesterone. The theoretical factors involved in making an accurate determination of the magnitude of alternative pathways of steroid biosynthesis were discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available