UP-REGULATION OF GLUTATHIONE SYNTHESIS IN RAT-KIDNEY BY METHYL MERCURY - RELATIONSHIP TO MERCURY-INDUCED OXIDATIVE STRESS

Prolonged exposure of rats to methyl mercury hydroxide (MMH) results, during the initial phase of exposure, in the rapid accumulation of mer cury as Hg2+ by kidney cortex and in a significant increase in oxidati ve stress, as characterized by the rate of formation of thiobarbituric acid reactive substances (TEARS) by renal mitochondria. These events are accompanied by a progressive increase in steady-state levels of th e mRNA encoding gamma-glutamylcysteine synthetase (GCS), the rate-limi ting enzyme in glutathione (GSH) synthesis and a 2- to 3-fold elevatio n in renal cortical GSH levels. The present study showed that the incr ease in GSH content was accompanied by a concomitant decrease in the r ate of TEARS formation. Subsequent to these initial phase events, cont inued MMH exposure was characterized by equilibration in the rate of r enal Hg2+ accumulation, a sharp decrease in both the TEARS formation r ate and GCS mRNA level, but sustained elevation of renal cortical GSH content. Depletion of GSH with buthionine sulfoximine subsequent to th e decline in the rate of TEARS formation did not result in a rebound o f the TEARS formation rate. These findings suggest that oxidative stre ss during the initial phase of MMH exposure is derived from the transf ormation of CH3Hg+ to Hg2+, which, in turn, induces the synthesis of H g2+- and/or oxidant-scavenging GSH molecules via the up-regulation of renal GCS mRNA. The findings also suggest that resistance to Hg2+-medi ated oxidative stress may be more closely associated with the capacity for up-regulation of GSH synthesis than with elevated GSH levels per se.