THE ROLE OF GENETIC AND ENDOCRINOLOGICAL FACTORS IN THE REGULATION OF RAT SERUM DOPAMINE- BETA-HYDROXYLASE ACTIVIT

Dopamine-beta-hydroxylase (DBH) is a Cu('2+)-containing enzyme that converts dopamine to norepinephrine. In mammals, DBH is localized in chromaffin tissue, central and peripheral adrenergic neurons, cerebrospinal fluid, and serum. Although serum DBH is believed to represent vesicular DBH that is released with norepinephrine during exocytosis, the evidence to date suggests that serum DBH levels are a poor index of sympathetic function. Nevertheless, the presence of a catecholamine biosynthetic enzyme is the serum, which is easily measureable and which presumably is derived from adrenergic neurons, offers a potentially useful biochemical measurement if the factors which regulate enzyme activity can be determined. Work in this laboratory and by others has led us to conclude that genetic and pituitary-thyroid factors are two principal regulators of serum DBH activity in man and rat. Pancreatic beta cell function may also play a role in regulating rat serum DBH levels. A change in steady state levels of an enzyme can occur by changes in production rate and/or changes in clearance rate. Our working hypothesis has been that altering the rate at which DBH is cleared from the circulation is a principal mechanism regulating enzyme levels.;Assessment of serum rat DBH disposal in rats was done by injecting a bolus of ('125)I-labelled purified bovine adrenal DBH (bDBH). The disappearance of immunoprecipitable DBH (IDBH) in the serum could be described by at least three components. Component l had a half-time of 8.5 min and an initial volume of distribution of 4.2 ml/100 g BS. Compartment 2 had a half-time of 89 min, and component 3 had a half-time of l.75-3.l days. At 2 hr post-injection, liver was the only tissue besides serum containing significant IDBH, while kidney contained large amounts of nonimmunoprecipitable radioactivity. Urinary excretion of ('125)I was determined over a 3 day period, and was found to be different from the calculated serum half-time. Experiments were also conducted using unlabelled (native) bDBH injected as a bolus into rats; disappearance rates were assessed by measuring enzymatic activity.;Following radiothyroidectomy in Sprague-Dawley male rats, serum DBH rose to 145% of control levels over a 4 wk period. Treatment of rats with thyroxine to induce hyperthyroid status resulted in a decrease of DBH to 75% control levels. Disappearance studies with native bDBH indicated that over a 5 hr period, hyperthyroid rats (low serum DBH) had a faster rate of bDBH disappearance compared to hypothyroid rats (high serum DBH). Short-term disappearance studies over a 30 min period also demonstrated a difference in bDBH clearance (hyperthyroid, initial half-time of disappearance = 10.2 min vs. hypothyroid, initial half-time of disappearance = 27.3 min).;The rate of disappearance of bDBH in inbred rat strains also showed differences corresponding to differences in endogenous serum DBH activity. Fischer 344 and Wistar/Furth female rats have basal serum DBH activities of 12.9 and 6.9 units/ml, respectively. Initial half-times of disappearance were 42 min for F344 and 25.6 min for WF.;Alloxan- and streptozotocin-induced diabetes mellitus in F344 and WF female rats is associated with a pronounced increase of serum DBH activity to 600% control levels. This increase in activity occurs rapidly over a 7 day period following the administration of the diabetogenic agent. The high serum DBH activity is associated with a decrease in the initial rate constant of disappearance (k) for exogenous bDBH. Insulin therapy of diabetic animals produces a significant decrease in the elevated serum DBH activity that is associated with an increase in the k for bDBH.;This work demonstrates that genetic, thyroidal, and pancreatic beta-cell factors regulate serum DBH activity in rats. The studies provide evidence that altered metabolic clearance rate of DBH is a principal mechanism via which these factors exert their regulation.