Rapid effect of treatment of psoriatic erythrocytes with the synthetic retinoid acitretin to increase 8-azido cyclic AMP binding to the RI regulatory subunit.
We have recently demonstrated a deficiency in the cyclic adenosine monophosphate (cAMP)-dependent protein kinases (PKA), the intracellular mediator of AMP, in psoriasis. This enzyme defect is expressed in fibroblasts and in red blood cells isolated from psoriatic patients. In these cells, the abnormality noted in cAMP binding to PKA correlates well with the severity of the disease and is corrected by long-term treatment with etretinate. In this study, we determined the effect of oral administration of acitretin in four psoriatic patients on the altered cAMP binding observed with the RI regulatory subunit of PKA in erythrocytes prepared from these patients. Acitretin (30 mg/day) induced a rapid (within 1 h) increase in the ability of the RI regulatory subunit of erythrocytes to bind the 8-azido[32P]cAMP photoaffinity analogue of cAMP. The maximal plateau for this effect of acitretin was observed within 24 h of treatment and preceded the clinical improvement of the disease. The effect of acitretin was dose-dependent, with the maximal response observed at 40 mg acitretin/d. In addition, the rapid exposure (15 min) of erythrocytes isolated from untreated patients exhibiting severe psoriasis to acitretin also promoted an increase in binding of 8-azido[32P]cAMP to the RI cAMP binding protein. Retinoic acid and 13-cis-retinoic acid were as efficient as acitretin in inducing the increase in binding of 8-azido[32P]cAMP to the RI regulatory subunit, whereas arotinoid was without effect. These results suggest that acitretin may act to modify PKA (the RI regulatory subunit) at the post-transcriptional level, and this may reflect, in part, on the mechanism of action of this synthetic retinoid. Further, monitoring this biochemical event may be helpful in determining the choice of retinoid therapy and in the management of its pharmacology.
Raynaud
F
F
Laboratoire de Physiopathologie du Développement, CNRS-Ecole Normale Supérieure, Paris, France.
Gerbaud
P
P
Bouloc
A
A
Gorin
I
I
Anderson
W B
WB
Evain-Brion
D
D
D017255:Acitretin / Q000494:pharmacology*; D000345:Affinity Labels; D001386:Azides / Q000378:metabolism*; D002469:Cell Separation; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011565:Psoriasis / Q000097:blood*; D013997:Time Factors
D000345:Affinity Labels; D001386:Azides; C017042:8-azidoadenosine-3',5'-monophosphate; D000242:Cyclic AMP; D011494:Protein Kinases; D017255:Acitretin