title: Phenytoin-mediated androgen metabolism in gingival fibroblasts. Effects of the antiandrogen finasteride and the alkaline phosphatase inhibitor levamisole.
abstract: OBJECTIVE
  This investigation attempts to identify the role of the alkaline phosphatase inhibitor levamisole (L) and the antiandrogen finasteride (F) on 5alpha-reductase activity in gingival fibroblasts, to elucidate mechanisms for phenytoin-induced gingival overgrowth.
  
  
  METHODS
  Human gingival fibroblasts were incubated with Eagle's MEM and 14C-testosterone/14C-4-androstenedione as substrates; effective concentrations of phenytoin (Ph), levamisole (L) and finasteride (F), alone and in combinations of (Ph + F) (Ph + L) were added to the incubate. After 24 h, the medium was analysed for steroid metabolites and quantified using a radioisotope scanner.
  
  
  RESULTS
  The metabolites isolated were 5alpha-dihydrotestosterone (DHT), 4-androstenedione (4-A) or testosterone (T) from each substrate. With 14C-T as substrate, Ph stimulated DHT synthesis by 1.7-fold, while F and L inhibited this activity by 1.8-fold and 34%, respectively (n = 6; P < 0.001). The combination of Ph + F reduced yields by 2.7-fold compared with Ph alone and Ph + L reduced DHT synthesis by 2.4-fold compared with Ph alone (n = 6; P < 0.001). When 14C-4-androstenedione was used as substrate, similar trends were identified.
  
  
  CONCLUSIONS
  These results suggest that the alkaline phosphatase inhibitor levamisole and the 5alpha-reductase inhibitor finasteride can substantially decrease the yields of DHT in fibroblasts, stimulated by phenytoin. This could be a potential target for reducing the gingival overgrowth caused by phenytoin.
authors.affiliation: Division of Periodontology, Guy's, King's and St Thomas' Dental Institute, King's Dental Hospital, London, UK. mena.soory@kcl.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Soory
authors.forename: A
authors.initials: A
authors.lastname: Suchak
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000328:Adult; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism*; D000735:Androstenedione / Q000378:metabolism; D000927:Anticonvulsants / Q000494:pharmacology*; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D018120:Finasteride / Q000494:pharmacology*; D019214:Gingival Overgrowth / Q000139:chemically induced* / Q000201:enzymology*; D005891:Gingivitis / Q000201:enzymology; D006801:Humans; D007978:Levamisole / Q000494:pharmacology*; D008875:Middle Aged; D010672:Phenytoin / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D000927:Anticonvulsants; D013196:Dihydrotestosterone; D007978:Levamisole; D013739:Testosterone; D000735:Androstenedione; D018120:Finasteride; D010672:Phenytoin; D000469:Alkaline Phosphatase