Designing newer and safter glucocorticoids

Glucocorticoids are used therapeutically for their anti-inflammatory and immunosuppressive properties. However, long-term glucocorticoid treatment is complicated by a number of side effects, mainly metabolic. It is known to exacerbate insulin resistance and worsen glycemic control in diabetics, accelerate osteoporosis and muscle wasting and cause fatty liver. Therefore glucocorticoid analogues that do not cause metabolic abnormalities, but retain their anti-inflammatory and immunosuppressive properties have long been sought by clinicians.

The authors of the paper, led by Carolyn Cummins of the University of Toranto in Canada, appear to have taken the first step towards achieving this goal. They have shown that a transcription factor called Liver X receptor (LXR) is required for dexamethasone (a synthetic analogue of glucocorticoids)-induced gluconeogenesis and hepatosteatosis. However, in LXR - beta knock-out mice, dexamethasone retained its immunosuppressive and anti-inflammatory effects.This showed that if scientists design glucocorticoid analogue which do not interact with LXR, such analogues may be anti-inflammatory and immunosuppressive without inducing metabolic side-effects.

It is known that glucocorticoids act by binding to cytoplasmic receptors (glucorticoid receptors) which translocate to the nucleus to induce or repress selective genes. LXRs are also a group of such receptors which can bind to selective genes and turn it on (induce) or turn it off (repress). However, the nature of glucocorticoid receptor interaction with LXR is unknown and future studies will be aimed at elucidating this.