The half-lives of intact and elastase cleaved human corticosteroid-binding globulin (CBG) are identical in the rabbit

Lewis, John G.; Saunders, Katie; Dyer, Arron; Elder, Peter A.

doi:10.1016/j.jsbmb.2015.01.020

Cited by 13 publications

(9 citation statements)

References 21 publications

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“…Native glycosylation of CBG in health and in pregnancy has been documented, but changes due to inflammation have not. Glycosylation of CBG appears to be important for protein stability, regulation of degradation, binding affinity, thermosensitivity and half‐life, although the half‐lives of haCBG and laCBG are identical consistent with the findings herein. Alterations in glycoforms may also be important for binding of specific receptors in target cells or accessibility of cortisol to the glucocorticoid receptor .…”

Section: Discussionsupporting

confidence: 85%

Reduced corticosteroid‐binding globulin cleavage in active rheumatoid arthritis

Nenke

Lewis

Rankin

et al. 2016

Clinical Endocrinology

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Section: Discussionsupporting

confidence: 85%

Reduced corticosteroid‐binding globulin cleavage in active rheumatoid arthritis

Nenke

Lewis

Rankin

et al. 2016

Clinical Endocrinology

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“…The dominant mechanism of cleavage in health is not known; both neutrophil elastase [8] and chymotrypsin [35] are known to cleave CBG and other tissue enzymes may also act on CBG's reactive centre loop to effect cleavage [13]. In rabbits, the plasma disappearance halflife for haCBG and laCBG are the same at 10 h, similar studies in humans are not yet reported [11]. Impaired cleavage may result from glycosylative changes to the CBG protein [13], stimulated by the extensive inflammatory [36] or hormonal milieu [37] of adipose tissue.…”

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confidence: 93%

Evidence of Reduced CBG Cleavage in Abdominal Obesity: A Potential Factor in Development of the Metabolic Syndrome

et al. 2016

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Corticosteroid-binding globulin (CBG) is involved in the regulation of cortisol delivery. Neutrophil elastase-mediated cleavage of high to low affinity CBG (haCBG to laCBG) induces cortisol release at inflammatory sites. Past studies have shown reduced CBG in obesity, an inflammatory state, particularly in central adiposity/metabolic syndrome. We performed an observational, cross-sectional study of the effects of obesity, age and sex on ha/laCBG in 100 healthy volunteers. Total and haCBG levels were 11% higher in women but did not vary with age or menopausal status. Total CBG levels were lower with increased body weight and waist circumference; laCBG levels were lower with increased body weight, waist circumference, body mass index and body fat; higher haCBG levels were seen with increased body fat. The relation between CBG and adiposity appeared to be driven predominantly by the metabolic syndrome group. The results suggest reduced CBG cleavage in central obesity, possibly contributing to the characteristic inflammatory phenotype of the central obesity and metabolic syndrome. The mechanism of gender differences in CBG levels is unclear.

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“…The elimination constant k C * e for human CBG * is reported to be the same as for uncleaved CBG in a study done in rabbits [17]. In humans the half life of CBG is approximately 5 days (range measured 4.6 to 6.0 days in five subjects) [71], i.e.…”

Section: Elastase Activitymentioning

confidence: 63%

“…During inflammation neutrophils may raise the level of neutrophil elastase (NE) in the blood. Elastase acts as an enzyme in transforming high-affinity, native CBG into a state CBG * with lower affinity [15,16,17,18]. Elastase causes an irreversible change in the reactive centre loop of CBG changing the conformational state of the protein from a S-state (S for stressed) into a R-state (R for relaxed), thus lowering the affinity by approximately a factor 10 [19,20,21].…”

Section: Model Development 211 the Bio-chemistry Of Plasma Cortisomentioning

confidence: 99%

Analysis and validation of a new extended method for estimating plasma free cortisol including neutrophil elastase and competition from other steroids

Gudmand-Hoeyer

Ottesen

2018

The Journal of Steroid Biochemistry and Molecular Biology

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A non-linear mechanistic model for the distribution of cortisol in plasma on free and bound forms is proposed. The influence of progesterone, testosterone and neutrophil elastase on the cortisol distribution in the blood is investigated. The activity of neutrophil elastase is directly included in the model with the concentration of elastase and the kinetic constants describing the activity of elastase collected in one single input variable. The model is very sensitive towards this input variable and fits data excellently, when it is allowed to be subject specific. The analysis shows that steroids such as testosterone with low affinity for corticosteroid-binding globulin (CBG) do not significantly influence the concentration of free cortisol. Progesterone has a high affinity for CBG, but low plasma concentrations compared to cortisol. Contrary to expectations, progesterone is shown to impact the distribution of cortisol in plasma both under circumstances with high levels as seen in pregnancy and during the normal menstrual cycle of women. Comparing the predictions of our model with predictions made with the equilibrium models by Coolens et al. [1], Dorin et al. [2] and Nguyen et al. [3] shows that the models differ considerably not only in their predictions for free cortisol, but also for cortisol on bound forms; i.e. bound to albumin, intact CBG and elastase-cleaved CBG. Disregarding some of the smallest terms of the model equations a reduced version of the model in form of a fourth order polynomial equation is obtained. The reduced version of the model performs almost identically to the full version and serves as a new formula for calculating the plasma free cortisol concentration.

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The half-lives of intact and elastase cleaved human corticosteroid-binding globulin (CBG) are identical in the rabbit

Cited by 13 publications

References 21 publications

Reduced corticosteroid‐binding globulin cleavage in active rheumatoid arthritis

Reduced corticosteroid‐binding globulin cleavage in active rheumatoid arthritis

Evidence of Reduced CBG Cleavage in Abdominal Obesity: A Potential Factor in Development of the Metabolic Syndrome

Analysis and validation of a new extended method for estimating plasma free cortisol including neutrophil elastase and competition from other steroids

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