Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 170-186).

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 122-136).

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 186-207).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 135-141).

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 91-124).

Pituitary hormones are known to alter sex steroid receptor levels in the liver, and possibly the actions of the steroids as well. Recently, two classes of estrogen binding proteins have been characterized in male rat hepatic cytosol: a high affinity, low capacity estrogen receptor, and a lower affinity, higher capacity sex steroid binding component (moderate affinity component). It is of interest that the moderate affinity component binds both androgens and estrogens. A high affinity, low capacity androgen receptor has not been convincingly demonstrated in rat hepatic cytosol. Therefore, we have investigated the relationship of the moderate affinity component to sex steroid modulation of hepatic aryl hydrocarbon hydroxylase (AHH) activity as a possible control mechanism. Because of the sexual dimorphism for hepatic drug and steroid metabolism known to occur in rat liver, we chose this model to study. We have shown that no sex difference exists for the binding of pH]-estradiol to the estrogen receptor from either immature or adult rats. However, the moderate affinity component does exhibit a sex difference. We did not detect binding to the moderate affinity component in adult female or immature rats of either sex. This site could normally only be measured in the adult male. These findings were consistent with the age and sex dependent elevation of male AHH activity. We have also observed that gonadectomy of the male reduced the levels of AHH activity and the capacity of the moderate affinity component in a testosterone reversible fashion. These results were obtained using either unlabeled estradiol or dihydrotestosterone (DHT) as competitors for [³H]-estradiol binding. Administration of mestranol reduced AHH activity and the capacity of the moderate affinity component in the male. The moderate affinity component was not detected in the pseudoherma-phroditic rat which resembled the female, rather than the male, with respect to control and induced AHH activity. Hypophysectomy of the female resulted in an increase in AHH activity and detection of the moderate affinity component. Hypophysectomy of the male reduced both the capacity of the moderate affinity component and AHH activity. Unlike the gonadectomized male, testosterone had no restorative effect on the levels of AHH activity or the capacity of the moderate affinity component in the hypophy-sectomized rat. Continuous infusion of rat growth hormone (rGH) reversed the effect of hypophysectomy on the increased AHH activity and capacity of the moderate affinity component in the female. Administration of rGH to the hypophysectomized male abolished the detection of the moderate affinity component and reduced AHH activity to control female levels. This suggested rGH may be the pituitary hormone involved in production of the female level of metabolism. The effects of prolactin were not as clear. Therefore, we have demonstrated the modulation of AHH activity by peripheral sex steroids, and the regulation of these parameters by rGH. We have shown, the capacity of the moderate affinity component to vary in a manner that paralleled changes in hepatic AHH activity in different physiological models. Changes in the estrogen receptor were not found to be consistent with changes in AHH activity in these models. We conclude that the moderate affinity component is comparable to the male hepatic cytosolic DHT-binding protein. Furthermore, this component is associated with sex steroid action on hepatic AHH activity in the male rat. Interestingly, we have also shown this component as well as the estrogen receptor, to bind polycyclic aromatic hydrocarbons. Both 3-methylcholanthrene and benzo[a]pyrene competed for [³H]-estradiol binding to the estrogen receptor and moderate affinity component. In addition, dioxin congeners demonstrated specificity for the estrogen receptor in the female. However, this was not observed for the estrogen receptor or moderate affinity component in the male. The significance of this is presently unclear. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 200-205).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser + 1 appendix.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 242-263).