Metabolic pathways of glutathione conjugates

Evidence for the inhibitory action of GS-conjugates on GST has been brought about by animal physiologists about a decade ago. Glutathione conjugates were recognized as competitive GST and GSSG reductase inhibitors in animals and plants (Ishikawa 1987, Ishikawa et al. 1994). In plants, evidence has been presented for the inhibition of corn and giant foxtail GST by the glutathione conjugate of tridiphane and other xenobiotic SG-conjugates (Lamoureux and Rusness 1989). The diuretic drug, ethacrynic acid (EA), is a reversible inhibitor of p-GST in animals (Ploemen et al. 1990, 1993, 1994) but also in plants (Schröder and Götzberger 1997). Norway spruce GSSG reductase (GR) has been shown to be inhibited at low con­cen­trations of the model S-(p-nitrobenzyl)glutathione conjugate (Schröder and Wolf, unpublished). Lamoureux and Rusness (1989) report the inhibition of spinach GR by several glutathione conjugates including S-(tridiphane)glutathione, S-(2,4-dinitro­phenyl)­glu­tathione and S-hexyl-glu­ta­thione. Interestingly, S-(propa­chlor)-glutathione and S-(methyl)-­glutathione were not inhibitory to this enzyme under identical experimental conditions.

Furthermore, reversibility of glutathione conjugation has been proven (Ishikawa 1987). Especially Michael-type additions to xeno­biotics may become un­stable when changes in pH occur, e.g. after transport into other compartments. Whether this is the principle underlying the transport of anthocyanins (Marrs et al. 1995) or medicarpin (Li et al. 1997) in the form of GS-conjugates into the vacuole via the GS-X-pump remains to be elucidated. GS-conjugates of anthocyanins have never been isolated and identified from plant cytosol or vacuoles. Besides chemical cleavage, the foreign compound may also be liberated by reverted action of GST itself under favorable conditions (Ishikawa et al. 1994).

The elimination of GS conjugates seems to be especially im­portant in cases where the conjugation leads to bioactivation, as in the case of halo­genated hydrocarbons which are known to be activated via GS-conju­gation to genotoxic electro­philes reacting with guanidine in DNA (Anders 1988, Ishikawa et al. 1994, Dekant et al. 1986, 1987). Rapid translocation of GS-conjugates by multi drug resistance (MDR) proteins in animals and other membrane ATPases is thought to prevent these deleterious effects (Ishikawa et al. 1994).