5-hydroxy-4-oxo-L-norvaline depletes intracellular glutathione: a new modulator of drug resistance

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.