Regulation of stimulated cyclic AMP synthesis by urocanic acid.
Urocanic acid (UCA) has been shown to mediate the UVB radiation-induced immunosuppression initiated in the skin by UV-induced isomerization from the trans to the cis isomer. However, the mechanism by which cis-UCA acts is still unclear. Therefore, the present study was undertaken to determine the effect of trans- and cis-UCA on cyclic adenosine 3',5'-monophosphate (cAMP) synthesis in human dermal fibroblasts, Golden Syrian hamster hepatocytes and in the human adenocarcinoma cell line, HT29. Neither trans- nor cis-UCA was able to stimulate cAMP synthesis directly in any of the models tested. In human dermal fibroblasts, cis-UCA, in contrast to trans-UCA, specifically inhibited cAMP synthesis induced by either prostaglandin (PG) E1 or PGE2 with a maximum inhibitory effect of 25-30% at cis-UCA concentrations greater than 1 microM and half-maximum inhibitory effect (EC50) observed at 35 nM. The effect of cis-UCA was not to stimulate phosphodiesterase and cAMP breakdown. The inhibitory effect of cis-UCA (an imidazole derivative) was not mediated through stimulation of the alpha 2-adrenergic receptor. The inhibitory effect of cis-UCA on stimulated cAMP synthesis was a function of the cell density and was only significant when the fibroblasts were confluent or postconfluent. In contrast to the studies with human dermal fibroblasts, an inhibitory effect of cis-UCA was not observed in either isolated hamster hepatocytes or HT29 cells, in which cAMP synthesis was stimulated by glucagon and vasoactive intestinal peptide, respectively. These results point to a possible regulation of cAMP synthesis in fibroblasts as one mechanism by which cis-UCA exerts its biological effect in the skin.
Bouscarel
B
B
Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA. beb@gwis2.circ.gwu.edu
Noonan
F
F
Ceryak
S
S
Gettys
T W
TW
Phillips
T M
TM
DeFabo
E C
EC
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019073:HT29 Cells; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects; D008647:Mesocricetus; D011810:Quinoxalines / Q000494:pharmacology; D014560:Urocanic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; D006632:Histamine; D000242:Cyclic AMP; D000527:Alprostadil; D014560:Urocanic Acid; D015232:Dinoprostone; D004837:Epinephrine