Additive inhibitory effect of calcipotriol and anthralin on ribonuclease P activity.
The effects of two antipsoriatic compounds, calcipotriol and anthralin, separately or in combination on ribonuclease P (RNase P), were investigated using a cell-free system from the slime mold Dictyostelium discoideum. RNase P is an ubiquitous and essential enzyme which endonucleolytically cleaves all tRNA precursors to produce the mature 5' end. The substrate for RNase P assays was an in vitro (32)P-labeled transcript of the Schizosaccharomyces pombe tRNA(Ser) gene supS1. Enzyme assays were carried out at 37 degrees in 20 microL 50 mM Tris-HCL 7.6 buffer, containing 10 mM NH(4)Cl, 5 mM MgCl(2), and 10% isopropanol. Calcipotriol or anthralin alone exerted a dose-dependent inhibitory effect on RNase P activity, with the former being more active than the latter in this respect. Simultaneous exposure of the enzyme to both drugs resulted in an enhancement of RNase P inhibition, which was additive. Considering the lack of structural similarities between the substrate (precursor tRNA) of RNase P and the tested drugs, it seems reasonable to suggest that their effects may be due to binding to allosteric inhibition sites of the enzyme. Although our in vitro findings cannot be directly extrapolated to the in vivo human condition, they do suggest that the inhibitory effects of calcipotriol and anthralin on tRNA biogenesis may be implicated in the mechanisms of their antipsoriatic action. Moreover, the additive inhibitory effect of these compounds on RNase P activity provides an experimental basis for their possible combined therapeutic application in the management of psoriasis.
Papadimou
E
E
Department of Biochemistry, School of Medicine, University of Patras, G26500, Patras, Greece.
Monastirli
A
A
Tsambaos
D
D
Drainas
D
D
D000287:Administration, Topical; D000818:Animals; D000875:Anthralin / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004023:Dictyostelium / Q000201:enzymology; D004357:Drug Synergism; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016337:RNA, Catalytic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043262:Ribonuclease P; D012568:Schizosaccharomyces / Q000201:enzymology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016337:RNA, Catalytic; C055085:calcipotriene; D004722:Endoribonucleases; C468368:RPP14 protein, human; D043262:Ribonuclease P; D002117:Calcitriol; D000875:Anthralin