Metabolic conversion as a pre‐receptor control mechanism for lipophilic hormones

Nobel, Stefan; Abrahmsén, Lars; Oppermann, U.

doi:10.1046/j.1432-1327.2001.02359.x

Cited by 77 publications

(59 citation statements)

References 159 publications

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“…Together, specific AKR1C family member may function as prereceptor regulators of the androgen or progesterone receptor by regulating the intracellular levels of DHT or progesterone. This mechanism of prereceptor regulation by ligand catabolism is well recognized for both the glucocorticoid and aldosterone receptors (Nobel et al, 2001). In contrast to these hormone-dependent tumors, increased expression of AKR1C1 and AKR1C2 has been observed in tumors of the aerodigestive tract.…”

Section: Discussionmentioning

confidence: 91%

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Lou

Du²,

Ji³

et al. 2006

Mol Pharmacol

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AKR1C2, also referred to as the human bile acid binder and 3␣-hydroxysteroid dehydrogenase type III, is a multifunctional oxidoreductase able to stereoselectively reduce steroids as well as oxidize or reduce polyaromatic hydrocarbons. Previously, this same protein was also identified by its robust induction by phase II inducers in HT29 cells. In HepG2 cells, both AKR1C2 and AKR1C1 (97% sequence homology) were induced by phase II inducers but not the highly related AKR1C3 and AKR1C4 family members (84% sequence homology). We now report the initial characterization of the proximal promoter of AKR1C2 in HepG2 cell line and the identification of a potent enhancer-like element responsive to phase II inducers located approximately 5.5 kilobases upstream from the transcription start site. DNA sequence analysis of this enhancer element revealed that it contained a consensus antioxidant response element (ARE), which was confirmed by mutation analysis.Treatment with phase II inducers leads to increased accumulation of nuclear factor-erythroid 2 p45-related factor (NRF) 2 in the nucleus, which was associated with increased binding to this ARE as determined by electrophoretic mobility shift assay. Transient transfection with Nrf2 increased the transcriptional activity of the ARE of AKR1C2 comparable with that observed with phase II inducers. Chromatin immunoprecipitation (ChIP) analysis also confirmed increased NRF2 binding to the ARE after induction by a phase II inducer. The AKR1C1 promoter also harbored this same ARE element in a highly homologous region, which was also bound by NRF2 in a ChiP analysis. No induction of the ARE of AKR1C2 was detected in Nrf2fibroblasts. The regulation of AKR1C2 by this distal ARE suggests that AKR1C2 detoxifies products of reactive oxidant injury, which has important implications for both hormone and xenobiotic metabolism.

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Section: Discussionmentioning

confidence: 91%

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Lou

Du²,

Ji³

et al. 2006

Mol Pharmacol

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“…This important physiological feature of TS, in which the action of its iodine-containing chemical messengers is finely tuned at the local target-cell level, is subserved by a set of ubiquitous reductive dehalogenases generally named iodothyronine deiodinases (Ds). Indeed, iodothyronine deiodination is the essential first step in the pre-receptor control mechanism of TH action (Nobel et al 2001). From an evolutionary perspective, Ds may be considered pivotal players in the emergence and functional diversification of both TS and their iodinated messengers.…”

Section: Introductionmentioning

confidence: 99%

Iodothyronine deiodinases: a functional and evolutionary perspective

Orozco¹,

Valverde-R²,

Olverá³

et al. 2012

Journal of Endocrinology

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From an evolutionary perspective, deiodinases may be considered pivotal players in the emergence and functional diversification of both thyroidal systems (TS) and their iodinated messengers. To better understand the evolutionary pathway and the concomitant functional diversification of vertebrate deiodinases, in the present review we summarized the highlights of the available information regarding this ubiquitous enzymatic component that represents the final, common physiological link of TS. The information reviewed here suggests that deiodination of tyrosine metabolites is an ancient feature of all chordates studied to date and consequently, that it precedes the integration of the TS that characterize vertebrates. Phylogenetic analysis presented here points to D1 as the oldest vertebrate deiodinase and to D2 as the most recent deiodinase gene, a hypothesis that agrees with the notion that D2 is the most specialized and finely regulated member of the family and plays a key role in vertebrate neurogenesis. Thus, deiodinases seem to be major participants in the evolution and functional expansion of the complex regulatory network of TS found in vertebrates.

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“…In humans, 11β-HSD1 converts cortisone into active cortisol [7,8,9,10,11]. In rodents, the inactive glucocorticoid is 11-dehydrocorticosterone and the active is corticosterone.…”

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confidence: 99%

Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

et al. 2002

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Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11β-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11β-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. Methods.BVT.2733 was given to spontaneously hyperglycaemic KKA y mice for 7 days using subcutaneous osmotic mini-pumps. Results. BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11β-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. Conclusion/interpretation. These results suggest that a selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1528[Diabetologia ( -1532

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Metabolic conversion as a pre‐receptor control mechanism for lipophilic hormones

Cited by 77 publications

References 159 publications

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Iodothyronine deiodinases: a functional and evolutionary perspective

Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

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