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Age-Related Reduction in Response of Hepatic Enzymes to 3,5,3'-Triiodothyronine Administration^*

HAROLD L. SCHWARTZ, MARY ANN FORCIEA, CARY N. MARIASH and JACK H. OPPENHEIMER

Division of Endocrinology and Metabolism, Department of Medicine, University of Minnesota Minneapolis, Minnesota 55455

Address requests for reprints to: Dr. Harold L. Schwartz, Department of Medicine, Mayo Memorial Building, University of Minnesota, 420 Delaware Street S. E., Minneapolis, Minnesota 55455.

Abstract

The relationship of age and responsivity to thyroid hormone of hepatic -glycerophosphate dehydrogenase (a- GPD) and malic enzyme (ME) was studied in rats 1, 2, 3, and 6 months of age. Basal enzyme levels as well as enzyme response to T₃ administration were correlated with nuclear content of T₃, nuclear T₃ receptor concentration, and receptor affinity. Basal enzyme levels of -GPD activity declined from 0.145 ± 0.012 to 0.079 ± 0.008 OD/min-mg protein (mean ± SD) between 1–6 months of age. ME levels also fell progressively from 28.6 ± 2.4 U/mg protein at 1 month to 6.2 ± 1.9 U/mg protein at 6 months. Comparable reductions in activity of both enzymes were observed when total cellular enzyme was related to DNA concentration. An age-related reduction of enzyme mass was suggested both by a proportional decrease in the V_max of the enzymes and by the identity of the equivalence point of ME at all ages against a specific anti-ME antiserum. Since the fractional rate of disappearance of both enzymes (t_1/2, 3.0 days) was unaltered in the older animals, it appears that the rate of appearance of enzyme is slowed as the animal matures. These reductions in enzyme activity were not related to alterations in either hepatic nuclear T₃ receptor concentrations or of the concentration of T.i bound to the receptor. Receptor concentrations (average, 0.43 ± 0.04 ng T₃/mg DNA) and affinity (ka = 4.9 ± 0.5 x 109 M^-1) were similar in all age groups. Nuclear T.t content was relatively constant at approximately 0.22 ng T₃/mg DNA. The response of the enzymes to single or multiple large daily doses of T.t sufficient to saturate the nuclear receptor sites was studied. The maximum response of both -GPD and ME 24 h after a single injection of 200 ng Ts/lOOg BW was 60–80% lower in rats at 6 months than in those at 1 month of age. These results suggest that in rats between 1–6 months of age there is a progressive diminution of responsivity of hepatic -GPD and ME to thyroid hormone. These data are also consistent with other recent findings which indicate significant modulation of thyroid hormone effects at a postreceptor level.

Footnotes

^* This work was supported by NIH Grant AM-19812.

Recipient of NIH Research Fellowship IF32 AG05125-01.

Trainee supported by NIH National Service Research Training Grant AM-07203.

Received December 1, 1978.