Hypoxoside is the major diglucoside isolated from the corms of the plant family Hypoxidaceae. It contains an unusual E-pent-1-en-4-yne 5-carbon bridging unit with two distal
catechol groups to which the
glucose moieties are attached. It is non-toxic for BL6 mouse
melanoma cells in tissue culture on condition that the
fetal calf serum in the medium is heat-inactivated for 1 hour at 56 degrees C in order to destroy endogenous
beta-glucosidase activity. The latter catalyses
hypoxoside conversion to its cytotoxic aglucone,
rooperol, which, when tested as a pure chemical, caused 50% inhibition of BL6
melanoma cell growth
at 10 micrograms/ml. Light and electron microscopy revealed that the cytotoxic effect of
rooperol manifested as vacuolisation of the cytoplasm and formation of pores in the plasma membrane. Indications of apoptosis were also found. Pharmacokinetic studies on mice dosed intragastrically with
hypoxoside showed that it was deconjugated by bacterial
beta-glucosidase to form
rooperol in the colon. Surprisingly, no
hypoxoside or
rooperol was detectable in the serum. Only phase II biotransformation products (sulphates and
glucuronides) were present in the portal blood and bile. In contrast, however, in human serum after oral ingestion of
hypoxoside, the metabolites can reach relatively high concentrations.
Rooperol metabolites isolated from human urine were non-toxic for BL6
melanoma cells in culture up to a concentration of 200 micrograms/ml. In the presence of
beta-glucuronidase, which released
rooperol from the metabolites, 50% growth inhibition was achieved at a 75 micrograms/ml metabolite concentration. The supernatant of a human
melanoma homogenate could also cause deconjugation of the metabolites to form
rooperol.(ABSTRACT TRUNCATED AT 250 WORDS)