Suppression of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and inflammation by the dehydroepiandrosterone analog 16alpha-fluoro-5-androsten-17-one and its reversal by NADPH liposomes.
Dehydroepiandrosterone and related steroids produce cancer-preventive and other potentially important therapeutic effects in laboratory animals. These steroids are potent uncompetitive inhibitors of mammalian glucose-6-phosphate dehydrogenase, the first enzyme in the pentose phosphate pathway. Inhibition of this pathway could have profound effects on the supply of 5-carbon sugars required for nucleic acid synthesis as well as on the availability of nicotinamide adenine dinucleotide phosphate (NADPH) and the cellular redox state. NADPH is a source of reducing equivalents for the production of oxygen free radicals, which act as intermediate messengers stimulating mitogenesis and up-regulating the inflammatory response. Using a mixture of NADPH and cationic liposomes to facilitate uptake of the normally impenetrable dinucleotide, we found that intradermal injections of NADPH-liposomes reversed the anti-inflammatory and anti-hyperplastic effects of the dehydroepiandrosterone analog, 16alpha-fluoro-5-androsten-17-one, in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate, whereas similar treatment had no apparent effect on the anti-hyperplastic and anti-inflammatory effect of corticosterone.
Schwartz
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Department of Microbiology, Temple University School of Medicine, Philadelphia, PA 19140, USA. lpashko@nimbus.temple.edu
Pashko
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D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002199:Capillary Permeability / Q000187:drug effects; D002273:Carcinogens; D002412:Cations; D003345:Corticosterone / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005609:Free Radicals; D006965:Hyperplasia / Q000139:chemically induced*; D007249:Inflammation / Q000139:chemically induced*; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D009249:NADP / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate
D000736:Androstenes; D000970:Antineoplastic Agents; D002273:Carcinogens; D002412:Cations; D005609:Free Radicals; D008081:Liposomes; C066783:16-fluoro-5-androsten-17-one; D003687:Dehydroepiandrosterone; D009249:NADP; D004247:DNA; D013755:Tetradecanoylphorbol Acetate; C106219:5-androstene-16-fluoro-17-one; D003345:Corticosterone