Tissue targets

5 Role of redox-active metals in the regulation of the metallothionein 

The isotope levels, ratios and changes with time in spleen and kidney in our study are consistent with a low level of heme uptake in these organs and some heme-hemopexin complexes reaching the bone marrow, but overall the data show that extra-hepatic uptake is low. It seems unlikely from the isotope recovery that endothelial cells lining the blood vessels express hemopexin receptors and we consider that hemopexin protects these cells by sequestering heme from them. 

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In humans, the hypothalamic-derived protein and the hormone noncovalent complexes are packaged in neurosecretory granules, then migrate along axons at a rate of 1 4 mm/h until they reach the posterior pituitary where they are stored prior to release into the bloodstream by exocytosis (67). Considerable evidence suggests that posterior pituitary hormones function as neurotransmitters (68) vasopressin acts on the anterior pituitary to release adrenocorticotropic hormone [9002-60-2] (ACTH) (69) as well as on traditional target tissues such as kidneys. Both hormones promote other important central nervous system (CNS) effects (9,70). 

The only commonly used radioisotope in this class is used in small (- IS.S MBq (500 -lCi) injected dose) quantities as a diagnostic for the evaluation of thyroid function. The compound is adininistered as Nal and these procedures are only possible owing to the favorable biological distribution of iodide. Up to 25% of the entire injected dose of iodide is accumulated in the thyroid with a very slow washout the rest is rapidly excreted in the urine. No other compound exhibits so high a ratio of concentration in a target tissue to that of other tissues. 

Principal factors that determine the likelihood of toxic effects being produced and their severity include the rates at which the causative substances (patent molecule, toxic metaboUte, or both) teach the tissues and the absolute amounts of materials to which the tissues ate exposed. These determine the dose of material received at the target tissues. 

Once they have elicited the appropriate action in their target tissue, hormones... 

The liver plays an important role in the endocrine system. The concentrations of hormones in plasma, and the activity of the glands which secrete them, are determined by the rate at which they are deactivated by the liver. The liver also has a major function in female reproduction since it is the target tissue of ovarian estrogen, to which it responds by producing the yolk protein vitellogenin. " Xenobiotics that affect either of these functions can therefore be considered to be potential endocrine disrupters. 

In humans, most steroids function as hormones, chemical messengers that are secreted by endocrine glands and carried through the bloodstream to target tissues. There are two main classes of steroid hormones the sex hormones, which control maturation, tissue growth, and reproduction, and the adrenocortical hormones, which regulate a variety of metabolic processes. 

Hormone (Section 27.6) A chemical messenger that is secreted by an endocrine gland and carried through the bloodslream to a target tissue. 

A gene gun is a device to introduce DNA into cells in vivo. The DNA is attached to gold particles, which are introduced under high velocity into the target tissue. 

An important safety issue of viral vectors is whether or not the recombinant viruses are able to replicate in the infected cells. Replication of viral vectors is unwanted in most gene-therapy approaches. Therefore, replication-defective vectors have been designed, which are able to perform only one initial infectious cycle within the target cell. In addition, replication-competent vectors have been designed, which are able to productively infect the target cell and to spread in the target tissue. 

Although MR also binds glucocorticoids, its main ligand in classical mineralocorticoid target tissues such as kidney and colon is aldosterone ( d 1.3 nM). This can be granted to the ability of 11 (3-hydioxysteroid dehydrogenase type II (11 (3-HSD II) to convert active cortisol into its inactive metabolite cortisone in these tissues. Since aldosterone is no substrate for this enzyme it can readily bind to MR, leading to exclusive occupation of the receptor by aldosterone. In contrast, no such mechanism exists in brain and presumably... 

To study the effect of an increased gene dosage of GR, Reichardt et al. (2000) and van den Brandt et al. (2007) generated rodent models of GR overexpression. These approaches confirmed that GR controls neuronal and immune functions in a dosage-dependent manner. These results highlight the importance of tight control of GR expression in target tissues and may explain... 

MR has a high affinity for mineralocorticoids such as aldosterone and DOC. In addition, MR also binds glucocorticoids although in mineralocorticoid target tissues this is prevented by the enzyme 11 (3-HSDII (see above). Since mineralocorticoids are no substrate for 11 (3-HSD II due to their cyclic 11,18-hemiacetyl-group, they are able to bind to MR despite the 1,000-fold lower concentration in plasma as compared with cortisol. 

Peroxisome Proliferator-Activated Receptors. Table 1 PPARa target tissues, cellular effects, and physiological effects... 

Interestingly, the antagonist activity of ICI and other antiestrogens has also been recently attributed to the ability of these compounds to induce degradation of the ER protein in estrogen target tissues. It is thought that... 

Table 1 Biological activities of ER ligands in selected target tissues...

Similarly, in developing Drosophila the response to wg is influenced by the relative abundance and ligand affinity of receptors expressed in the target tissue. A synthesis of the available data from all species suggests that the response to a specific Wnt signal in vivo is influenced both by the particular Wnt protein secreted and by the receptors and other downstream molecules present in the target tissue. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. 

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