Phenytoin-mediated androgen metabolism in gingival fibroblasts. Effects of the antiandrogen finasteride and the alkaline phosphatase inhibitor levamisole.
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.
Soory
M
M
Division of Periodontology, Guy's, King's and St Thomas' Dental Institute, King's Dental Hospital, London, UK. mena.soory@kcl.ac.uk
Suchak
A
A
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
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