Mechanism of inhibition of growth of 3T3-L1 fibroblasts and their differentiation to adipocytes by dehydroepiandrosterone and related steroids: role of glucose-6-phosphate dehydrogenase.
Dehydroepiandrosterone (DHEA) and certain structural analogues block the differentiation of 3T3-L1 mouse embryo fibroblasts to adipocytes. These steroids also are potent uncompetitive inhibitors of mammalian glucose-6-phosphate dehydrogenases (G6PDs). We provide direct evidence that treatment of the 3T3-L1 cells with DHEA and its analogues results in intracellular inhibition of G6PD, which is associated with the block of differentiation: (i) Levels of 6-phosphogluconate and other products of the pentose phosphate pathway are decreased; (ii) the magnitude of these decreases depends on the potency of steroids as inhibitors of G6PD and on concentration and duration of exposure, and it is accompanied by a proportionate block of differentiation; (iii) in cells exposed to 16 alpha-bromoepiandrosterone (a more potent inhibitor of G6PD than DHEA) at concentrations that block differentiation, introduction of exogenous 6-phosphogluconate in liposomes raises the levels of 6-phosphogluconate and other products of the pentose phosphate pathway and partially relieves the steroid block of cell growth and differentiation.
Shantz
L M
LM
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Talalay
P
P
Gordon
G B
GB
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005942:Gluconates / Q000502:physiology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors; D051379:Mice; D010428:Pentosephosphates / Q000502:physiology*; D013329:Structure-Activity Relationship
D005942:Gluconates; D010428:Pentosephosphates; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone; D005954:Glucosephosphate Dehydrogenase; C008884:6-phosphogluconic acid