Abstract

After 2 weeks of goitrogen treatment [propylthiouracil (PTU), 0.02% in drinking water], the thyroids of rats increased to 280% of control wet weight, 270% of dry weight, and 250% of control DNA content. Two phases of growth were apparent, an initial hypertrophy phase lasting 3 days (increase in cell size and gland weight with no detectable increase in DNA) and a hyperplastic phase (increase in DNA with histological evidence of cell proliferation) starting at 3-4 days and continuing through 14 days. The cyclic AMP-dependent protein kinase activity ratio (-cyclic AMP/+cyclic AMP) showed a biphasic pattern during the 2-week thyroid growth period, with maxima at day 1 (132% of control) and day 6 (148% of control). Ornithine decarboxylase (EC 4.1.1.17), the initial enzyme in polyamine biosynthesis, showed a similar biphasic pattern with a 6- to 7-fold elevation in activity at 2-3 days and a 4-fold elevation at 6 days. S-Adenosyl-L-methionine decarboxylase (EC 4.1.1.50), the enzyme which catalyzes spermidine synthesis, was elevated 4-fold at 9 days of treatment. The thyroid total supernatant protein kinase activity (+cyclic AMP) increased to 160% of control by 4 days, returning to control by 14 days of PTU treatment. The thyroid had 10% Type I activity and 90% Type II cyclic AMP-dependent protein kinase activity. The specific activity of both Types I and II remained unchanged for the first 2 days of PTU treatment. Both types increased to 150% of control by 4 days. Type I remained elevated throughout the remainder of the 14 days, in contrast to Type II, which decreased conspicuously to control levels by 6 days. A single injection of thyroid-stimulating hormone (TSH, 1.0 unit/100 g of body weight, i.p.) resulted in a 20-fold increase in thyroid ornithine decarboxylase activity by 4 hr. The same dose of TSH produced only a 3-fold induction of ODC in rats hypophysectomized 2 weeks previously. The thyroid specific activity of Types I and II protein kinase was only 55% and 57% of control, respectively, in these unresponsive rats. Thyroids from rats chronically stimulated for 14 days showed an increase in ornithine decarboxylase following TSH administration similar to that of control rats. Changes in the activation as well as specific activity of Types I and II protein kinase during hypertrophy and hyperplasia underlie the complexity of a cyclic AMP-mediated response.