Modulatory effects of indomethacin on androgen metabolism in human gingival and oral periosteal fibroblasts.
The non-steroidal anti-inflammatory agent indomethacin (I) suppresses gingival inflammation and alveolar bone resorption. Androgens particularly 5 alpha-dihydrotestosterone (DHT) have anabolic effects on connective tissue and bone matrices. Human oral periosteal fibroblasts (HPF) and gingival fibroblasts (HGF) instigate healing in inflammatory periodontal lesions. The aim of this investigation was to compare the modulatory effects of I on the metabolism of two androgen substrates in human oral periosteal and gingival fibroblasts in culture. Monolayer cultures of both cell types (5(th)-9(th) passage) were established in Eagle's MEM and incubated with 14C-testosterone/14C-4-androstenedione and serial concentrations of I (0.5-50 microg/ml) for 24 h. The steroid metabolites were solvent extracted from the medium, separated by TLC and quantified using a radioisotope scanner. Both androgen substrates were metabolized mainly to DHT and 4-androstenedione/testosterone respectively, expressing 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity in both HPF and HGF. There were 51% and 73% increases in the levels of DHT over controls, with HGF and HPF respectively (n = 6; n = 4, P < 0.01) in response to I at 1-5 microg/ml, often reaching control values at 50 microg/ml. The expression of 17 beta-HSD activity showed less stimulation than the levels of DHT. Both androgen substrates were effective in this metabolic conversion, which is applicable to healing responses in both males and females in vivo. There were 57% increases (n = 4; P < 0.01) over controls, in the formation of androstanediol from 14C-4-androstenedione at 10 microg of I, in HPF. This transformation may regulate androgen action in androgen-dependent tissue. In addition to its anti-inflammatory properties, indomethacin can contribute to anabolic reparatory responses, by increasing the expression of steroid metabolizing enzymes in gingival and periosteal fibroblasts, in the inflammatory periodontal lesion.
Tilakaratne
A
A
Department of Periodontology, Faculty of Dental Sciences, University of Peradeniya, Sri Lanka.
Soory
M
M
D000328:Adult; D000704:Analysis of Variance; D000728:Androgens / Q000378:metabolism*; D000735:Androstenedione / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D013196:Dihydrotestosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010521:Periosteum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D000728:Androgens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D007213:Indomethacin