Inhibition of the conversion of 3T3 fibroblast clones to adipocytes by dehydroepiandrosterone and related anticarcinogenic steroids.

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHEA) and related steroids have widespread protective effects against spontaneous and chemically induced tumors, suppress weight gain without affecting food intake, and depress lipogenesis. We have observed that DHEA and 16 alpha-bromoepiandrosterone (16 alpha-bromo-3 beta-hydroxy-5 alpha-androstan-17-one) block the conversion to adipocytes of the 3T3-L1 and 3T3-F442A mouse embryo fibroblast clones. The arrest of lipogenic conversion was assessed by measurements of lipid biosynthesis and the specific activity of cytosolic glycerol-3-phosphate dehydrogenase. In the presence of 215 microM DHEA or 30 microM 16 alpha-bromoepiandrosterone, the increase in glycerol-3-phosphate activity was only 50% of that of fully differentiated control cells. The blocking effects were concentration dependent and were observed only if the differentiation stimuli and the blocking steroid were present simultaneously. Concentrations of these steroids that almost completely blocked conversion to adipocytes were not cytotoxic. Although the relation between structure and blocking activity of steroids is complicated by metabolism of DHEA in these cultures, a strong correlation exists between the structural requirements for blocking differentiation and for inhibition of glucose-6-phosphate dehydrogenase. The 3T3-L1 and 3T3-F442A preadipocyte clones are, therefore, appropriate and convenient model systems for the analysis of the mechanism of the anticarcinogenic effects of DHEA and related steroids.