Propylthiouracil alters the expression and activity of glutathione-dependent enzymes in the mouse olfactory mucosa

Propylthiouracil (PTU) is an anti-thyroid drug that reportedly can impair olfactory function in humans and mice. In the mouse, PTU treatment disrupts survival and differentiation of olfactory precursor neurons. While the mechanism responsible for this effect is not understood, it is suspected that these changes are consequent to localized toxicity due to PTU metabolism. In vitro and in vivo studies in other biological systems demonstrate that PTU can significantly alter glutathione S-transferase (GST) enzyme expression and activity. The localization of GST biotransformation enzymes in basal cells, sustentacular cells and Bowman's glands of the olfactory mucosa suggests that these cells play a significant role in olfactory physiology. This study investigated the effects of PTU treatment, T(4) replacement therapy and thyroidectomy on GST expression, GST and glutathione peroxidase (GSH-PX) activity in mouse olfactory tissue. One month treatment with PTU revealed a significant decrease in expression of GST alpha (37%) as identified by Western blot analysis. In contrast, no change in GST mu expression was observed after 1 month of treatment. Concomitant treatment with T(4) caused a significant induction of GST alpha, and mu isozymes. GST enzyme activity significantly decreased after 1 month of PTU treatment (53%) and remained suppressed, despite the presence of exogenous T(4). GSH-PX activity significantly decreased after 1 month of PTU treatment (30%) and remained at control levels with T(4) supplementation. Thyroidectomy caused a 25% reduction in olfactory GST alpha expression. Total GST and GSH-PX activity were not altered in these animals. Supplementation with T(4) in thyroidectomized animals prevented the suppression of GST alpha expression. These results suggest that the combined action of localized PTU toxicity and altered levels of circulating thyroid hormone contribute to PTU-mediated abnormalities in the olfactory system.