Metabolism of antitumor acylfulvene by rat liver cytosol

Illudins are novel compounds from which a potent class of antitumor agents, called acylfulvenes, have been synthesized. The model illudin, illudin S, has marked in vitro and in vivo toxicity but displays a poor therapeutic in dex. The toxicity of illudin S is believed to involve a combination of enzy matic reduction and chemical reaction. Enzymatic reduction by a cytosolic N ADPH-dependent enzyme produces an aromatic metabolite, as does reaction wit h thiols. Acylfulvene is formed from illudin S by reverse Prins reaction. A cylfulvene is 100-fold less toxic in vitro and in vivo than illudin S but p ossesses marked antitumor efficacy in vivo, thus displaying opposite proper ties from illudin S. For this reason we investigated the in vitro metabolis m of acylfulvene. Incubation of acylfulvene with NADPH and rat liver cytoso l yielded two metabolites. One metabolite, the aromatic product, is similar to that obtained with illudin S in this in vitro system and was anticipate d. The other metabolite, the hydroxylated product, was not expected and no corresponding metabolite for illudin S could be detected. The production of this hydroxylated. metabolite from acylfulvene may explain, in part, the i ncreased antitumor activity of novel acylfulvenes as compared with the illu dins. (C) 1998 Elsevier Science Inc.