The effects of epidermal growth factor, interleukin-1, and phenytoin, alone and in combination, on C19 steroid conversions in fibroblasts.
The formation of the biologically active metabolite 5 alpha-dihydrotestosterone (DHT) from testosterone in response to phenytoin (Ph), interleukin-1 (IL-1), and epidermal growth factor (EGF) was investigated. The androgen DHT stimulates matrix synthesis in connective tissue and bone. Duplicate incubations were performed with confluent human gingival fibroblasts, 14C-testosterone, and optimal stimulatory concentrations of IL-1 (5 IU/ml), EGF (10 ng/ml), Ph (5 micrograms/ml), Ph + EGF, and Ph + IL-1 respectively for 24 hours in Eagle's MEM at 37 degrees C. The medium was then analyzed for radioactive metabolites. Similar incubations were performed with human gingival tissue using 14C-4-androstenedione as substrate in the presence or absence of EGF, Ph, and EGF + Ph. In the cell lines studied, EGF stimulated DHT and 4-androstenedione synthesis by 20% (n = 5; P < 0.01; Wilcoxon signed rank statistic for paired observations). IL-1 stimulated DHT and 4-androstenedione synthesis by 2-fold (n = 6; P < 0.01). Ph stimulated DHT and 4-androstenedione synthesis by 2-fold increases (n = 3; P < 0.01). Combinations of phenytoin and EGF stimulated DHT and 4-androstenedione synthesis by 33% and 37% greater than the effect of phenytoin alone (n = 3; P < 0.01). Combinations of Ph and IL-1 caused a 45% increase in the amount of DHT formed and a 66% increase in 4-androstenedione when compared to the effect of phenytoin alone (n = 3; P < 0.01). 14C-4-androstenedione was converted to DHT and testosterone by human gingival tissue. There were 2-fold, 4-fold, and 2.5-fold increases in DHT synthesis and 5-fold, 2-fold, and 6-fold increases in the formation of testosterone in response to EGF, Ph, and EGF + Ph respectively (n = 3; P < 0.01). EGF and IL-1 present in inflammatory exudate may have implications on phenytoin-induced overgrowth via the steroid metabolic pathway.
Soory
M
M
Department of Periodontology, King's College School of Medicine and Dentistry, London, UK.
Kasasa
S C
SC
D015067:17-Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003238:Connective Tissue / Q000378:metabolism; D003470:Culture Media; D013196:Dihydrotestosterone / Q000378:metabolism; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D013739:Testosterone / Q000378:metabolism*
D002250:Carbon Radioisotopes; D003470:Culture Media; D004338:Drug Combinations; D007375:Interleukin-1; D019275:Radiopharmaceuticals; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D010672:Phenytoin; D004815:Epidermal Growth Factor; D015067:17-Hydroxysteroid Dehydrogenases