Oscillations of hepatic delta-aminolevulinic acid synthetase produced by estrogen: a possible role of "rebound induction" in biological clock mechanisms.

Abstract

6-Aminolevulinic acid synthetase (ALA synthetase) is the first and rate-controlling enzyme of the heme biosynthetic pathway.1-4 In liver the enzyme can be induced in high levels (50X normal or more) by various compounds which produce experimental porphyria, particularly allylisopropylacetamide.'-3 5-7 The increased excretion of porphyrin precursors in acute intermittent porphyria, an inborn error of metabolism, has been shown to result from a high hepatic level of ALA synthetase.8'9 Various physiological factors are now being shown to affect the enzyme level in liver. The induction of hepatic ALA synthetase is blocked by carbohydrate administration in animals,2 and diet studies suggest that the genetically mediated induction of hepatic ALA synthetase in acute intermittent porphyria is also blocked by carbohydrate administration.'0 Hydrocortisone exerts a permissive on the induction of this enzyme. The first suggestion of an effect of estrogens on hepatic porphyrin metabolism came from clinical observations by Watson of patients with latent hepatic porphyria.'2 Administration of estrogens to patients with carcinoma of the breast or prostate was followed in certain instances by photocutaneous manifestations of hepatic porphyria. It is now clear that both cutaneous and neurological manifestations can sometimes by precipitated by estrogen administration to patients with latent hepatic porphyria. The effects of both endogenous and exogenous sex hormones in a large series of patients with porphyria have been carefully summarized by Zimmerman et al.'3 Studies of stilbestrol14 and estradiol'5 administration to patients with hepatic porphyria and data from estrogen-treated liver cells in a tissue culture medium3 both indicate that estrogen induces hepatic ALA synthetase. More recently, evidence has been presented that steroids of the 5t3 configuration (etiocholane and pregnane derivatives) induce hepatic ALA synthetase.'6 The present studies demonstrate that a single minute dose of the naturally secreted estrogen, estradiol, given intravenously to rats produces a series of oscillations of the level of hepatic ALA synthetase which continue for days. The rise in hepatic ALA synthetase level occurs as a rebound following an initial decline. Materials and Methods.-Estradiol was diluted from an initial suspension of 1 mg/ml saline to a final concentration in solution of 4 ,ug/ml saline. Each rat was given 1 ml of the solution intravenously over a period of approximately one minute. In the experiments where the curve of oscillation of hepatic ALA synthetase was amplified by use of allylisopropylacetamide, this compound was administered subcutaneously in a dose of 300 mg/kg five hours before sacrifice. Sprague-Dawley females, ovariectomized three weeks prior to each experiment