No abstract

No abstract

Abstract. Diabetes mellitus exerts a sex-dependent effect on hepatic drug metabolism in the rat and it has been suggested that this is due to a reduction in serum androgen levels. This study shows that the effect of diabetes is only seen in the presence of androgen and that testosterone can reverse the effect of diabetes on drug metabolism. Diabetes, however, does not consistently cause a reduction in serum testosterone. Diabetes and androgens, therefore, are postulated to interact in their effects on drug metabolism by action on a common mediator. It is suggested that this mediator is growth hormone, which is known to be affected by the androgens and insulin and to be involved in sex differences in drug metabolism in the rat.

The role of thyrotropin-releasing hormone (TRH) in the physiological control of prolactin release from the anterior pituitary gland is well established.' Only in the past decade, however, have substantial advances been made in understanding the cellular mechanisms by which the releasing hormone achieves these effects. Much credit for our present enlightenment is due to the pioneering work of Armen Tashjian and his colleagues who, over 20 years ago, developed a number of rat pituitary tumor cell lines, collectively termed GH cells.* Certain of these clonal cell lines, in particular GH3 and GH4C1 cells, contain many receptors for TRH on their cell surface3 and respond to their occupancy by enhancing both prolactin release and synthesis.' Although it is naive to imagine that these cells are entirely homogeneous in terms of their sensitivity to the tripeptide, there is little doubt that analysis of biochemical data obtained from these cells is much less open to misinterpretation than is corresponding data derived from hemipituitaries or cultured anterior pituitary cell preparations. This report will outline recent advances in TRH signal transduction mechanisms and will emphasize that TRH receptor antagonists, albeit of limited selectivity, are available and can contribute to these studies. TRH-STIMULATED INOSITOL LIPID METABOLISMIn recent years, the ubiquitous association of stimulated inositol Lipid breakdown and cell activation in response to a wide variety of receptor stimulants has become e~i d e n t .~The characteristic intracellular signals-an increase in cytosolic free calcium and activation of protein kinase C-are known to derive from the formation within the cell of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and 1,2diacylglycerol (DAG). These result from hydrolysis of phosphatidylinositol 4 3bisphosphate (PtdIns(4,5)P~) by a phosphodiesterase enzyme that Downes and Michel14 have termed phosphoinositidase C. The production of two intracellular messengers as an immediate response to occupation of one receptor is a novel

4 While the ability of benzodiazepines to interact with the GABA receptor-chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+-and (--4-methylmidazolam (Ro 21-5656 and Ro 21-5657) to compete with TRH at its receptor. 5 Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRHinduced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH-stimulated GH3 cells up to 60min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH-induced phosphatidylinositol 4,5-bisphosphate hydrolysis is not transient.