Metabolism of corticosterone in mammalian and avian intestine

11␤-hydroxysteroid dehydrogenase (11␤HSD) catalyzes the conversion of the glucocorticoids, corticosterone and cortisol, to the respective derivatives 11-dehydrocorticosterone and cortisone. The recent findings underline the importance of this enzyme in excluding glucocorticoids from mineralocorticoid receptors. In the present study, 11␤HSD activity was compared in the intestine of herbivorous (guinea pig), omnivorous (rat), and granivorous (hen) animals, i.e., in animals in which the Na ؉ transport either is or is not regulated by aldosterone under normal conditions and in which the plasma levels of individual glucocorticoids are different. Slices of various intestinal segments were incubated in the presence of corticosterone or 11-dehydrocorticosterone, and the steroids were extracted and analyzed by HPLC. In the mammalian intestine, the activity of 11␤HSD was very low (approaching zero) in aldosterone-insensitive segments (duodenum, jejunum) but significant activity was revealed in aldosterone-sensitive segments (ileum, cecum, and proximal and distal colon). In comparison with the rat, the guinea pig large intestine exhibited significantly higher activity of 11␤HSD. There was no detectable reductase activity (conversion of 11-dehydrocorticosterone to corticosterone) in any intestinal segments of either species. Unexpectedly, no 11␤HSD activity was observed in the avian intestine. It was found that, in contrast to the mammalian intestine, corticosterone was metabolized to 20-dihydrocorticosterone while 11-dehydrocorticosterone was converted to 11-dehydro-20-dihydrocorticosterone. The distribution of 20-hydroxysteroid dehydrogenase (20HSD) activity in the avian intestine was homogenous along the intestine and did not correlate with the mineralocorticoid sensitivity of intestinal segments. To trace different cosubstrate dependence of 11␤HSD and 20HSD, homogenates of ileum and distal colon were incubated with NAD ؉ /NADH or NADP ؉ / NADPH, respectively. In accordance with slice experiments mammalian intestine displayed only oxidation of corticosterone to 11-dehydrocorticosterone and NAD ؉ preference. In avian intestine, the metabolite formed from corticosterone was 11-dehydrocorticosterone in the presence of NAD ؉ or NADP ؉ whereas in the presence of NADPH 11-dehydro-20-dihydrocorticosterone and 20-dihydrocorticosterone were formed. Given the wide similarity between mineralocorticoid regulation of epithelial transport in mammals and birds, the unexpected finding of differences in the metabolism of corticosterone suggests that role of 20HSD is to allow aldosterone occupancy of mineralocorticoid receptors. 1998 Academic Press The enzyme 11␤-hydroxysteroid dehydrogenase (11␤HSD) interconverts active glucocorticoids (cortisol, corticosterone) to their 11-dehydro forms (cortisone, 11-dehydrocorticosterone), which normally exhibit very weak corticosteroid activity in vivo. There is now considerable evidence suggesting that 11␤HSD decreases the concentration of intracellular glucocorticoids to levels that allow aldosterone to occupy nonselective mineralocorticoid receptor

Peripheral circadian clocks are diversely affected by adrenalectomy

<p>Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (<i>Bmal1, Per1-3, Cry1, RevErbα, Rora</i>), clock-output genes (<i>Dbp, E4bp4</i>) and a glucocorticoid- and clock-controlled gene (<i>Gilz</i>) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT). Adrenalectomy did not affect the phase of clock gene rhythms but distinctly modulated clock gene mRNA levels, and this effect was partially tissue-dependent. Adrenalectomy had a significant inhibitory effect on the level of <i>Per1</i> mRNA in VAT, liver and jejunum, but not in kidney and splenocytes. Similarly, adrenalectomy down-regulated mRNA levels of <i>Per2</i> in splenocytes and VAT, <i>Per3</i> in jejunum, <i>RevErbα</i> in VAT and <i>Dbp</i> in VAT, kidney and splenocytes, whereas the mRNA amounts of <i>Per1</i> and <i>Per2</i> in kidney and <i>Per3</i> in VAT and splenocytes were up-regulated. On the other hand, adrenalectomy had minimal effects on <i>Rora</i> and <i>E4bp4</i> mRNAs. Adrenalectomy also resulted in decreased level of <i>Gilz</i> mRNA but did not alter the phase of its diurnal rhythm. Collectively, these findings suggest that adrenalectomy alters the mRNA levels of core clock genes and clock-output genes in peripheral organs and may cause tissue-specific modulations of their circadian profiles, which are reflected in changes of the amplitudes but not phases. Thus, the circulating corticosteroids are necessary for maintaining the high-amplitude rhythmicity of the peripheral clocks in a tissue-specific manner.</p

Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli.

Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, α-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream