Phenytoin-mediated androgen metabolism in gingival fibroblasts - Effects of the antiandrogen finasteride and the alkaline phosphatase inhibitor levamisole

Objectives: 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. Material and 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. Conclusion: 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.