Thyroid hormone stimulates γ-glutamyl transpeptidase in the developing rat cerebra and in astroglial cultures

Hypothyroidism in the developing rat brain is associated with enhanced oxidative stress, one of the earliest manifestations of which is a decline in the level of glutathione (GSH). To investigate the role of thyroid hormone (TH) on GSH homeostasis, the effect of TH on gamma-glutamyl transpeptidase (gamma GT), the key enzyme involved in the catalysis of GSH, was studied. Hypothyroidism declined the specific activity of cerebral gamma GT at all postnatal ages examined (postnatal day 1-20) with a maximum inhibition of 42% at postnatal day 10. Intraperitoneal injection of TH to 15-day-old rat pups increased the specific activity of gamma GT by 25-30% within 4-6 hr. Treatment of primary cultures of astrocytes by TH also enhanced the specific activity of gamma GT by 30-40% within 4-6 hr. The induction of gamma GT by TH was blocked by actinomycin D or cycloheximide. gamma GT is an ectoenzyme that is normally involved in the catabolism of GSH released by astrocytes. In the presence of the gamma GT-inhibitor, acivicin, GSH released in the culture medium of astrocytes increased linearly for at least 6 hr and TH had no effect on this accumulation pattern. In the absence of acivicin, GSH content of the medium from TH-treated cells was significantly lower than that of untreated controls due to activation of gamma GT by TH and a faster processing of GSH. Because the products of gamma GT reaction are putative precursors for neuronal GSH, the activation of gamma GT by TH may be conducive to GSH synthesis in neurons and their protection from oxidative stress. (c) 2005 Wiley-Liss, Inc.