The effect of surgical stress on the in vitro metabolism of thyroxine by rat liver, kidney, and brain. In man, acute stress, like extensive surgery, leads to a rapid and prolonged decrease in serum T3 concentrations. The present study was carried out to investigate the mechanisms that underly the abrupt decrease in T3-neogenesis that occurs in response to acute surgical stress. Male Sprague-Dawley rats, surgically thyroidectomized, and treated with 1.2 micrograms T4/100 g BW/day, underwent wide vertical and horizontal incisions extending into the abdominal cavity while receiving light ether anesthesia. Different dietary manipulations were performed to investigate the superimposed influence of reduced carbohydrate and caloric intake on T3-neogenesis. The metabolism of 125I T4 labeled in its outer (phenolic) ring was investigated in liver, kidney, and brain homogenates of animals killed 48 h after surgery. In liver, values for the proportion of T4 degraded and the percent generation of T3 and iodide were unaffected by laparotomy. The percent T3 generation in experiments with 25 nM T4 concentration was 3.7 +/- 1.24% (mean +/- SD) in fed control animals given free access to 5% glucose, 3.4 +/- 0.67% in unoperated controls given a restricted amount of chow and 5% glucose, and 3.8 +/- 0.67% in operated animals given free access to chow and 5% glucose. As expected, T3 neogenesis in livers from unoperated animals was significantly reduced in rats fasted for 48 h and this reduction was similar in laparotomized rats fasted for 48 h after surgery. As in the liver, no effect of laparotomy on T4 metabolism in kidney and brain homogenates was observed. Finally, serum total T4 and T3 concentrations were not affected by surgery. It is concluded that acute surgical stress in thyroidectomized T4 replaced rats does not influence T4 metabolism in liver, kidney, and brain homogenates or affect the serum T4 and T3 concentrations. Since thyroid secretion of T4 (and T3) was eliminated and careful attention was paid to caloric intake in this rat model, previously reported abnormalities in serum thyroid hormone concentrations and T3-neogenesis in various states of nonthyroidal illness in man and rat, including surgery, are probably contributed to by thyroid secretion of T4 (and T3) and caloric deprivation, especially carbohydrate. 