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

Abstract

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 γ-glutamyl transpeptidase (γ GT), the key enzyme involved in the catalysis of GSH, was studied. Hypothyroidism declined the specific activity of cerebral γ 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 γ GT by 25-30% within 4-6 hr. Treatment of primary cultures of astrocytes by TH also enhanced the specific activity of γ GT by 30-40% within 4-6 hr. The induction of γ GT by TH was blocked by actinomycin D or cycloheximide. γ GT is an ectoenzyme that is normally involved in the catabolism of GSH released by astrocytes. In the presence of the γ 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 γ GT by TH and a faster processing of GSH. Because the products of γ GT reaction are putative precursors for neuronal GSH, the activation of γ GT by TH may be conducive to GSH synthesis in neurons and their protection from oxidative stress.