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 mercury as Hg2+ by kidney cortex and in a significant increase in oxidative stress, as characterized by the rate of formation of thiobarbituric acid reactive substances (TBARS) by renal mitochondria. These events are accompanied by a progressive increase in steady-state levels of the mRNA encoding gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in glutathione (GSH) synthesis and a 2- to 3-fold elevation in renal cortical GSH levels. The present study showed that the increase in GSH content was accompanied by a concomitant decrease in the rate of TBARS formation. Subsequent to these initial phase events, continued MMH exposure was characterized by equilibration in the rate of renal Hg2+ accumulation, a sharp decrease in both the TBARS formation rate and GCS mRNA level, but sustained elevation of renal cortical GSH content. Depletion of GSH with buthionine sulfoximine subsequent to the decline in the rate of TBARS formation did not result in a rebound of the TBARS formation rate. These findings suggest that oxidative stress during the initial phase of MMH exposure is derived from the transformation of CH3Hg+ to Hg2+, which, in turn, induces the synthesis of Hg(2+)- and/or oxidant-scavenging GSH molecules via the up-regulation of renal GCS mRNA. The findings also suggest that resistance to Hg(2+)-mediated oxidative stress may be more closely associated with the capacity for up-regulation of GSH synthesis than with elevated GSH levels per se.
Woods
J S
JS
Department of Environmental Health, School of Public Health and Community Medicine, University of Washington, Seattle 98195, USA.
Ellis
M E
ME
D000818:Animals; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000378:metabolism; D008767:Methylmercury Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D008767:Methylmercury Compounds; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D005721:Glutamate-Cysteine Ligase; C020771:methylmercury hydroxide; D008628:Mercury; D005978:Glutathione