Liver (human)

male phenotype and secondary sexual characteristics (44). Its contribution to metabolism of cortisol is uncertain.

Metabolism to Polar Steroids

The cytochrome p450 microsomal enzyme 6^-hy-droxylase and 20-reductase (20a- and 20^-HSDs) are mainly expressed in the liver (45-48). The former is upregulated by glucocorticoids. These pathways account for only a small fraction ( < 10%) of cortisol metabolites but may be more important in the metabolism of synthetic glucocorticoids (see below). 20a- and 20^-HSDs also catalyse further reduction of tetrahydrocorticoids to cortols and cortolones. Finally, p450scc and 21-oxidase catalyse the terminal oxidation steps to 11-hydroxy-etiocholanolone and cortolic/cortolonic acids, respectively.

Sites of Cortisol Metabolism

Inactivation of Cortisol

The most active metabolism of Cortisol occurs in liver and kidney. It is hard to quantify the contribution of other sites but 11 ^-HSD2 expressed at lower levels in large organs such as lung, skin and (perhaps) vasculature may be important, as may 5a-reductase expressed in adipose stromal cells and skin.

Estimates of hepatic clearance of cortisol are not available in humans because of the difficulty of obtaining portal venous samples and measuring hepatic blood flow. Experiments in animals in isolated perfused livers (49) suggest that the majority of cortisol is inactivated, principally to A-ring reduced metabolites, on single pass through the liver. However, this is offset by reactivation of cortisone into cortisol by hepatic 11^-HSD1 (26), so that the overall gradient of cortisol across the liver may be quite small.

In humans, around 10% of cortisol is extracted on single pass through each kidney (50). A minority is filtered in the glomerulus and excreted as urinary free cortisol, but most is inactivated to cortisone by 11^-HSD2 in the distal nephron. This has been confirmed by observations that nephrectomized patients have very low circulating cortisone levels (51), and by measurement of arteriovenous differences in 11a-3H-cortisol from which the 3H label is cleaved irreversibly by 11£-HSD2 (Figure 18.3) (50).

Reactivation of Cortisol

The half-life of cortisol in the circulation is about 90 minutes. However, the half-life of 11a3H-cortisol, from which the 3H is removed by 11^-HSD type 2, is about 40 minutes. This discrepancy suggests that there is significant reversible 'shuttling' between cortisol and its 11-oxidized metabolite. The only major metabolic pathway of cortisol which is reversible (Figure 18.2) is its interconversion with cortisone. There is a large pool of cortisone in plasma available for reactivation and widespread expression of the 11^-HSD1 enzyme for which cortisone is the principal substrate. Plasma levels of cortisol ( ~ 500 nM peak in the morning and ~ 100 nM trough in the evening) are higher than those of cortisone ( ~ 70 nM), but, unlike cortisol, cortisone is not highly protein bound and is not subject to marked diurnal variation (26). So, especially in the evening, free cortisone concentrations in plasma exceed those of cortisol. This cortisone is derived both from generation by 11^-HSD2 in kidney, and from adrenocortical secretion. 11^-HSDs are expressed in the adrenal gland (40,52-54) and cortisone is elevated in plasma from the adrenal vein (26,55).

The capacity to reactivate cortisone to cortisol was the basis for the first therapeutic use of glucocorticoids, which relied upon administration of cortisone acetate. After oral administration, relatively little cortisone is detected in peripheral plasma (Figure 18.4) consistent with extensive first pass metabolism in the liver. Indeed, efficient reductase activity of 11^-HSD1 has been confirmed in isolated perfused liver in vitro (49), and by ar-teriovenous sampling in vivo (26). In addition, however, endogenous cortisone in the systemic circulation may be reactivated to cortisol by 11^-HSD1 in many other sites (Table 18.1). Thus, elevated ratios of cortisol/cortisone relative to circulating ratios have been detected in lung (bronchoalveolar lavage fluid) (56), and subcutaneous adipose tissue (arteriovenous sampling) (57). The absolute rate at which cortisol is generated by this peripheral reactivation has not been compared with the rate of adrenocortical de novo synthesis and secretion, since use of suitable tracer steroids has yet to be reported.

Impact of Cortisol Metabolism on Tissue Response

The effects of corticosteroids are mediated by in-tracellular receptors which function as transcription factors inducing and repressing the expression of a host of target genes. Many such transcriptional effects are mediated by direct contact of the receptors with target gene DNA via 'glucocorticoid response elements' in their 5' promoter regions (Figure 18.5), others occur via actions upon other DNA-bound transcription factors, such as AP1, NFkB and CREB. The corticosteroid receptors are members of the steroid/thyroid intracellular receptor superfamily (Table 18.3) which are widely expressed. Almost without exception, the access of ligands to receptors in this family is modulated by 'pre-receptor' metabolism, and tissue-specific


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