Metabolism and action of glucocorticoids and interference with the antioxidant redox pathway

Disturbance of endocrine systems and signaling pathways can lead to severe disorders. Such disorders can have endogenous as well exogenous origin. The awareness of environmentally occurring xenobiotics that are able to directly interfere with and modulate the action of endogenous hormones has driven the need for mechanistic studies. Although there is a vast literature on potentially endocrine disrupting chemicals, there are only few studies investigating disturbance of glucocorticoid action by xenobiotics, despite of the importance of these hormones. In this work, the organotin dibutyltin (DBT) was identified as an endocrine disruptor of the glucocorticoid pathway. Its extensive use in plastic industry, as well as an antifouling agent explains its occurrence in water and seafood. In the present study, we were able to show that DBT disturbs GR mediated anti-inflammatory effects. Furthermore, DBT was found to potentiate NFκB mediated production of the pro-inflammatory cytokines IL-6 and TNFα in macrophages. The presented work therefore contributes to the mechanistic understanding of DBT-induced immunotoxicity.
There are several therapeutic purposes accompanied by the modulation of the endogenous hormone system. In traditional medicines natural compounds, and plant extracts are applied since centuries for different purposes, including the treatment of diseases such as diabetes and hypertension. The benefits of evidence based medicines, even if their mechanisms of action are unknown, are widely accepted. In conventional medicine the re-awareness of naturally derived compounds and their huge potential promoted the investigation of the underlying specific mechanisms of action of such compounds over the last decades. In this context, the present work investigated effects of eriobotrya japonica, a plant used for anti-diabetic treatment in Chinese medicine. The project aimed to identify potential constituents that are active on 11β-HSD1. Several pentacyclic triterpenes were isolated and further characterized. These compounds included potent and, compared with 11β-HSD2, selective 11β-HSD1 inhibitors such as corosolic acid and urosolic acid, as well as urosolic acid derivatives with only low inhibitory potential but considerable synergistic effects. Inhibitors for research and/or therapeutic purposes ideally display high selectivity to avoid miss-leading interpretations of their action. Furthermore, therapeutic intervention requires selective inhibitors to prevent unexpected side effects. The most famous triterpenoid inhibiting 11β-HSD enzymes is glycyrrhetinic acid (GA), present in liquorice. GA is a potent, but non-selective inhibitor of both 11β-HSD isoformes. Recently, GA was used as a starting compound and chemical modifications of its back-bone enabled the development of potent and specific inhibitors against 11β-HSD2. The present work describes the characterization of these novel 11β-HSD2 inhibitors. The inhibitors were characterized for their inhibitory potential by determining their IC50 values and selectivity for 11β-HSD enzymes as well as their species specificity by using human and mouse enzymes. Moreover, the capability for the inhibition of the endogenous 11β-HSD2 enzyme in intact cells was investigated.
Selective inhibition of 11β-HSD1 was proposed over the last years as promising drug target to cope with the consequences of obesity and diabetes type II and the metabolic syndrome. The present study supports beneficial effects of 11β-HSD1 inhibition from a different point of view. Our data suggest that excessive glucocorticoid activation by 11β-HSD1 may interfere with the antioxidant redox pathway by a GR-dependent manner. The present work describes the active glucocorticoid-dependent inhibition of classic target genes of the Nrf2-Keap1 detoxification pathway on both mRNA as well as protein level. Thus, the work supports the existence of important cross-talk between GR and Nrf2. Pathologically enhanced glucocorticoid activation, as exists in patients with alcoholic liver disease (ALD), may impair the cellular detoxification capacity.
In conclusion, the presented studies highlight different aspects of the interference of small molecules with the glucocorticoid pathway, including the endocrine disruption by DBT and inhibition of 11β-HSD enzymes, by natural and synthetic compounds. The identification and characterization of specific inhibitors against 11β-HSD1 and 11β-HSD2 offers valuable mechanistic tools. Further, the work provides evidence for the interference of 11β-HSD1 action with the antioxidant redox pathway and therefore may contribute to a deeper understanding of the pathology of locally enhanced glucocorticoids.
In conclusion, the presented studies should contribute to a better understanding of glucocorticoid related pathologies and the underlying mechanisms.