Activities of aldo-keto reductase 1 enzymes on two inhaled corticosteroids: implications for the pharmacological effects of inhaled corticosteroids

Abstract

Inhaled corticosteroids (ICS) are a mainstay anti-inflammatory therapy for the management of asthma. ICS are synthetic glucocorticoids that are structurally similar to the natural active human glucocorticoid cortisol. Steroid transforming enzymes of the aldo-keto reductase (AKR) family, namely AKR1D1 (5β-steroid reductase) and AKR1C1-4 (ketosteroid reductases) are implicated in the systemic metabolism of cortisol in liver. In this study, the activities of these AKR1 enzymes on cortisol and two ICS compounds budesonide (BUD) and flunisolide (FLU) were investigated. It was found that the catalytic efficiency of AKR1D1 for the reduction of the double bond in cortisol was 4- and 10-fold higher than the catalytic efficiencies of AKR1D1 with FLU and BUD, respectively. This suggests that compared to cortisol, for which the 5β-reduction is a major metabolic pathway, a lower degree of systemic (hepatic) metabolism of BUD and FLU via AKR1D1 takes place. In addition, BUD potently inhibited AKR1D1 and AKR1C4, the key steroid metabolizing enzymes in liver, which may disrupt endogenous steroid hormone metabolism and thus contribute to BUD-induced systemic effects. Activities of AKR1C1-3 on cortisol and the two ICS compounds (targeting the 20-keto group) suggest these enzymes may be involved in the local (lung) metabolism of these glucocorticoids.

Fig.1

(A) Chemical structures of cortisol, BUD and FLU and (B) metabolic reactions catalyzed by AKRs.

Fig.2

Inhibition of AKR1D1 and AKR1C4 reactions by BUD and FLU.