Assessment of steroid enzymes action in children and adolescents with obesity
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Rising prevalence of obesity has become an important impulse to investigate basic mechanisms involved in regulating the energy balance. It is widely accepted that steroids are potent factors affecting glucose, fat, and protein metabolism. Our study was aimed to analyze differences in the total amount of selected enzymes implicated in steroid metabolism in a group of children suffering from obesity and those with normal weight, further subdivided according to sex and pubertal stage. Data were obtained from 187 Caucasian children and adolescents, including 113 patients (63 girls, 50 boys) with obesity and 74 (34 girls, 40 boys) normal weight volunteers. Standard clinical examinations were performed in both groups. To evaluate the impact of puberty, preadolescent children and those with advanced puberty were assessed separately. Urine steroid excretion profiles were analyzed using gas chromatography/mass spectrometry method. Children with obesity revealed several changes in in the total amount of steroid enzymes as assessed by the relevant metabolite proportions, compared to their norm weight peers. Girls showed a significant increase in the activity of 11βHSD1, while boys demonstrated a relevant elevation in 20αHSD action. Regardless of sex, children with obesity showed an increase in the activity of 5β-reductase + 3αHSD complex and a decrease in the involvement of 11βOH-lase. The effect is attenuated when consider pre- and pubertal subgroups. We hypothesize that changes in the activity levels of selected enzymes may be a compensatory mechanism to limit the glucocorticoid exposure of key target tissues as well as to improve metabolic control and reduce long-term complications of obesity.Keywords:
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Anabolic steroid
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Summary Sensitive and specific displacement analysis methods for the assay of steroid hormones in small volumes of plasma are described. Plasma sex steroid and gonadotrophin hormone patterns were determined throughout a number of normal menstrual cycles. The mean cycles showed patterns which were similar to those described by other workers. However, examination of individual cycles provided information which may contribute to our understanding of menstrual cycle regulation with particular reference to the pattern of 17a‐hydroxyprogesterone and steroid‐gonadotrophin interactions.
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ENDOCRINE DISRUPTING CHEMICALS ALTER STEROID TRANSPORT PROTEINS AND STEROID FREE AND BOUND FRACTIONS
The effects of endocrine disrupting chemicals (EDCs) on the development of sexually dimorphic characteristics in vertebrates have been studied extensively for over sixty years. Throughout this time , studies have focused mainly on the disrupted steroidogenesis and steroid signaling pathways. Often , only freely suspended plasma steroids were reported , despite the fact that a large portion of plasma steroids are bound to circulating steroid transport proteins. When bound to transport proteins , steroids have reduced binding to steroid nuclear and membrane receptors and increased binding to transport protein receptors. Thus , steroid transport proteins regulate steroid activity. Sexually dimorphic characteristics of tissues require specific concentrations and milieus of steroids during development and disruption of these steroid milieus leads to abnormal differentiation. Therefore , it is likely that the developing organism also requires specific free and bound ratios depending on the sex. However , few studies have addressed the effects of EDCs on sexual dimorphism of steroid transport proteins and steroid fractions despite the impact that transport proteins have on steroid signaling , development , and physiology. To address this , I first summarize the current literature on the regulation of transport proteins , their interactions with steroid signaling , and how transport proteins are affected by environmental contaminates. These findings are culminated into a new model of steroid signaling that includes transport protein mediated pathways. Second , using HPLC-MS/MS , I show that a normal sexual dimorphism exists in free and bound steroid ratios for the steroids progesterone , corticosterone , testosterone , and 17[beta]-estradiol. Additionally , I found a normal sexual dimorphism in the ratio of the bound precursor progesterone , to its potent metabolites , with females having higher progesterone to metabolite ratios than those in males. When exposed to the model EDC , Vinclozolin , sexual dimorphism of free and bound steroids was lost , with males and females responding to disruption in different ways. The disruption of plasma steroid ratios was found in the absence of changes to liver steroid transport protein concentrations. The results of this study show that steroid free and bound ratios as well as ratios of precursor to metabolite steroids can be altered by EDCs. This study clearly shows that future work in determining effects of EDC should also determine free and bound fractions of steroids to better understand effects of contaminants.
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The metabolism of zetidoline, a new neuroleptic, in the rat and the dog has been studied. From the urine of rats and dogs given 5 mg/kg of [2-14C] zetidoline orally, unchanged drug and five metabolites were isolated and the structures of four of them assigned by physicochemical analysis. They are: metabolite B, 4'-hydroxy-3'-chlorophenyl zetidoline; metabolite D, zetidoline without the aryl group; metabolite E, the 6'-hydroxy-4'-beta-D-glucuronide of metabolite B, and metabolite F, the 4'-beta-D-glucuronide of metabolite B. The plasma levels of zetidoline and its metabolites after iv administration show that the drug is rapidly excreted and/or metabolized in both animal species. The plasma radioactivity in the dog consists mainly of the pharmacologically active (neuroleptic) metabolite B, whereas in the rat it consists of the more polar metabolites. After oral administration, elimination in both species occurs mostly via the kidneys. In the dog, within a 24-hr period, 6.2 +/- 0.4% of the dose is accounted for as unchanged zetidoline, 7.6 +/- 0.5% as metabolite B, 10.1 +/- 0.7% as the unidentified metabolite C, and 21.4 +/- 1.1% as metabolite F. In the rat, over the same period, zetidoline is present in traces, metabolite B accounts for 6.9 +/- 0.3% of the dose, metabolite D for 6.6 +/- 0.9%, metabolite E for 15.2 +/- 1.4%, and metabolite F for 31.7 +/- 2.2%.
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