Receptor occupancy organization

Between 5,000 and 100,000 GR molecules are found within almost every cell of the organism. The affinity constant for cortisol comes to around 30 nM, which is in the range of the concentration of free hormone in the plasma under normal conditions. Consequently, receptor occupancy can be expected to be 10-70%. This suggests that changes in cortisol secretion such as under stress conditions, directly translate into alterations in GR occupancy, leading to transcriptional responses. 

Figure 3 Simulations (A, B, and C) showing pulmonary (upper line) and systemic (lower line) receptor occupancies for a hypothetical beta-2-adrenergic drug that display the desired (pulmonary) and undesired (systemic) effect by occupying two different types of receptors. Cases A, B, and C show the occupancy profiles for pulmonary and systemic effects when the receptor affinity of the drug in the lung (for beta-2 receptors) remains unchanged but decreases (for beta-1 receptors) at the systemic organs (compare with A). Thus pulmonary selectivity is achieved at the pharmacodynamic level. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D.

All of those substances have specific binding sites at the respective organs. The occupation of these receptors result in a transmitter-characteristic pattern of effects. These transmitters gain increasing interest as therapeutic targets as well as mechanisms for unwanted biological effects. 

In contrast to the clear evidence of adverse effects of PFCAs on male reproductive organs in animal studies, evidence from epidemiological studies is far less clear-cut. Impaired semen quality was associated with high levels of PFCs in non-occupationally exposed males in a Danish study (Joensen et al. 2009) but not in other studies (Raymer et al. 2012 Toft et al. 2012 Specht et al. 2012). No associations between semm PFOA and reproductive hormone levels were noted in an occupationally-exposed (Olsen et al. 1998) or Northern European (Specht et al. 2012) males. There is no information available regarding PFC activity at the androgen receptor. In summary, >C8 PFCAs appear to alter reproductive hormone homeostasis in male rodents and possibly in nonhuman primates without direct effects on fecundity in standard reproductive toxicity studies, possibly because of the high resilience of rodents to anti-fertility effects. The available data indicate that either FTOH may not be toxic to the male reproductive tract or are significantly less potent at these endpoints than PFCAs. 

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