On the mechanism of toxicity of illudins: the role of glutathione.
Illudin M and illudin S, antitumor sesquiterpenes from Omphalotus illudens, have been found to react with thiols in a pH-dependent manner. The optimum pH values for reaction of illudin M with methyl thioglycolate, cysteine, and glutathione were 5.8, 5.6, and 6.1, respectively, and pseudo-first-order rate constants at 25 degrees C (10-fold excess of thiol) were 44 x 10(-3), 11.5 x 10(-3), and 11.3 x 10(-3) min-1. In all cases, thiol added to the alpha, beta-unsaturated ketone giving an unstable intermediate. Subsequent loss of the tertiary hydroxyl and opening of the cyclopropane ring afforded a stable aromatic product. The toxicity of illudin S to HL60 cells was increased by lowering glutathione levels in the cells and vice versa. General toxicity and antitumor activity of illudins are discussed in the light of these results.
McMorris
T C
TC
Department of Chemistry, University of California, San Diego, La Jolla 92093.
Kelner
M J
MJ
Wang
W
W
Moon
S
S
Taetle
R
R
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001711:Biotransformation; D004247:DNA / Q000378:metabolism; D005978:Glutathione / Q000502:physiology*; D005982:Glutathione Transferase / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C052673:illudin M; D004247:DNA; D005982:Glutathione Transferase; C008105:illudin S; D005978:Glutathione