M. Tagashira et al., 5-hydroxy-4-oxo-L-norvaline depletes intracellular glutathione: a new modulator of drug resistance, BIOS BIOT B, 63(11), 1999, pp. 1953-1958
To search for compounds that reverse the drug resistance induced by glutath
ione (GSH), an original screening system to detect intracellular GSH deplet
ers was established. Among 8843 microbes derived from the soil samples test
ed, the extracts of two Streptomyces species, named KS6701 and KS8846, lowe
red the intracellular GSH level of Saccharomyces cerevisiae 5 x 47. From bo
th the microbes, 5-hydroxy-4-oxo-L-norvaline (HON) was isolated as the acti
ve compound. At a concentration of 50-100 mu g/ml, HON also decreased the G
SH/protein level of the human ovarian tumor cell line, 2008/C13*5.25 and re
versed its resistance to cisplatin. We also investigated the mechanism of t
he depletion. HON had little effect on gamma-glutamglcysteine synthetase (g
amma-GCS) or glutathione synthetase, but HON decreased the quantity of thio
l substances when it was spontaneously reacted with them. This suggested th
at the GSH depletion by HON occurred through a mechanism different from tha
t of buthionine sulfoximine, a selective gamma-GCS inhibitor.