Suppression of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and inflammation by the dehydroepiandrosterone analog 16 alpha-fluoro-5-androsten-17-one and its reversal by NADPH liposomes

Dehydroepiandrosterone and related steroids produce cancer-preventive and o ther potentially important therapeutic effects in laboratory animals. These steroids are potent uncompetitive inhibitors of mammalian glucose-6-phosph ate dehydrogenase, the first enzyme in the pentose phosphate pathway, Inhib ition 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 red ox state. NADPH is a source of reducing equivalents for the production of o xygen free radicals, which act as intermediate messengers stimulating mitog enesis and up-regulating the inflammatory response. Using a mixture of NADP H and cationic liposomes to facilitate uptake of the normally impenetrable dinucleotide, we found that intradermal injections of NADPH-liposomes rever sed the anti-inflammatory and anti-hyperplastic effects of the dehydroepian drosterone analog, 16 alpha -fluoro-5-androsten-17-one, in mouse skin treat ed with 12-O-tetradecanoylphorbol-13-acetate, whereas similar treatment had no apparent effect on the anti-hyperplastic and anti-inflammatory effect o f corticosterone. (C) 2001 Elsevier Science Ireland Ltd. All rights reserve d.