Glucocorticoid hormones mechanism

A second explanation of the ability of oxidative stress to cause DNA damage is that the stress tri ers a series of metabolic events within the cell that lead to activation of nuclease enzymes, which cleave the DNA backbone. Oxidative stress causes rises in intracellular free Ca, which can fiagment DNA by activating Ca -dependent endonucleases (Orrenius etal., 1989 Farber, 1990 Ueda and Shah, 1992) in a mechanism with some of the features of apoptosis (see Wyllie, 1980). An example of apoptosis is the killing of immature thymocytes by glucocorticoid hormones, which activate a cell-destructive process that apparently involves DNA fragmentation by a Ca -dependent nuclease. 

The biosynthesis and secretion of these adrenal cortical hormones are influenced by the hypothalamus-pituitary axis and the adrenocorticotrophic hormone (ACTH) and its associated feedback mechanisms (Figure 10.3.1). The secretions of ACTH are pulsatile, and they are influenced more by the central nervous system and the pituitary gland than the glucocorticoid feedback mechanisms. 

Glucocorticoid hormones regulate syntheses of specific mRNA species [14,15]. Interaction of the steroid-receptor complex with highly localized regions of chromatin is essential for this induction, but little of the molecular basis for this activation mechanism is understood. The primary action of glucocortiocoids is very rapid thus, any alterations in chromatin which are essential for this activation would be observed within a few minutes after steroid addition. Also, it is possible that proteins known to be associated with transcriptionally active genes, such as the HMG 14 and 17 [8, 9], are important. 

The synthesis of ADR from NA in the adrenal medulla also appears to be under complex control in vivo. The N-methyl transferase enzyme responsible for this conversion is potently inhibited by the product ADR (Kt = 50-100 /iM). Since the endogenous concentration of ADR in the adrenal medulla is very high, it is probable that the synthesis of ADR is controlled by product inhibition of the N-methyl transferase. In addition a long-term control mechanism exists in that the synthesis of the N-methyl transferase enzyme is dependent on continued exposure of the medullary tissue to high concentrations of glucocorticoid hormones secreted by the surrounding adrenal cortex. Enzyme activity falls after hypophysectomy. and can be restored by the administration of ACTH or glucocorticoids. 

Whereas it is conceivable that a CRH/vasopressin hyperdrive contributes to behavioral, emotional, and hormonal symptoms of mood disorders, the question remains which mechanisms mediate this hyperactivity of CRH and vasopressin-secreting neurons. The gene expression of both neuropeptides is suppressed by ligand-activated glucocorticoid receptors. The efficiency of this negative feedback action of circulating corticosteroids depends on the number of corticosteroid receptors, their affinity, and the degree of interaction with other factors (e.g., heat shock protein) involved in the transcription machinery. 

Prompt effects such as initial feedback suppression of pituitary ACTH occur in minutes and are too rapid to be explained on the basis of gene transcription and protein synthesis. It is not known how these effects are mediated. Among the proposed mechanisms are direct effects on cell membrane receptors for the hormone or nongenomic effects of the classic hormone-bound glucocorticoid receptor. The putative membrane receptors might be entirely different from the known intracellular receptors. 

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