Since 5, 5′-diphenylhydantoin (DPH) decreases specific nuclear receptor binding of T3, the possibility that DPH might affect thyroid activity was examined by measurement of the activity of rat hepatic cytosol malic enzyme (ME) and mitochondrial α-glycerophosphate dehydrogenase (α-GPD) after DPH administration. Groups of athyreotic rats, prepared by thyroidectomy and 131I administration, were injected with vehicle (V), DPH, T3, or a combined dose of DPH and T3 for 48 h. The rats were then killed, and liver fractions were prepared for the measurement of ME and α-GPD activities. Compared with the V group, DPH treatment resulted in a significant increase in mean ME activity in four experiments; the mean ME activity for all studies was 2.2-fold greater than that of the V group (P < 0.001). A significant increase in mean α-GPD activity was not observed in DPH-treated rats. T3 treatment resulted in a mean 31.5-fold increase in ME activity and a 10.9- fold increase in α-GPD activity. The magnitude of T3 induction of both enzymes was substantially attenuated by simultaneous injection of DPH, to 54–66% of the activity induced by T3 alone (P < 0.001). Pair-feeding a T3-injected group and the DPH plus T3 group did not result in a decrease in the activity of either enzyme. Moreover, the observed changes did not appear to result from alterations in enzyme determinations or from significant changes in cytosol or mitochondrial protein concentration, cytosol T3, or plasma glucose. Although DPH-induced changes in the fractional rate of enzyme metabolism cannot be excluded, it is possible that changes in enzyme activities observed after DPH injection resulted from an interaction between DPH and the nuclear T3 receptor. If so, based on the effects observed in the present studies, DPH might be classified as a partial thyroid agonist.
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