INDUCTION OF METALLOTHIONEIN SYNTHESIS BY GLUTATHIONE DEPLETION AFTERTRANS-STILBENE AND CIS-STILBENE OXIDE ADMINISTRATION IN RATS

To investigate the relationship between glutathione (GSH) depletion an d metallothionein (MT) synthesis, the effects of substrates and an inh ibitor of GSH S-transferases on concentrations of hepatic GSH, zinc (Z n) and MT were studied in rats. Trans-stilbene oxide (TSO) is an induc er of drug metabolizing enzymes and also a substrate of GSH S-transfer ase, whereby it covalently reacts with and depletes GSH. The hepatic G SH level was decreased to 25% of the control 2 h after injection of TS O, and returned to the control level by 24 h. TSO significantly increa sed hepatic concentrations of Zn and MT in a dose-dependent manner. Tw o isoforms of MT (MT-I and MT-II) were increased by TSO; MT-II was the dominant form. Pretreatment with buthionine sulfoximine (BSO), an inh ibitor of GSH synthesis, enhanced MT synthesis itself as well as that induced by TSO and cis-stilbene oxide (CSO). On the contrary, injectio n into rats of perfluorodecanoic acid (PFDA), an inhibitor of GSH S-tr ansferase, resulted in a decrease in basal levels of Zn, and prevented the increase in MT synthesis by TSO and CSO, These results suggest th at the decrease of GSH concentration in the liver which causes oxidati ve stress conditions may be related to MT induction.