Corticosteroid metabolism in isolated perfused rat liver and kidney. Experimental studies with emphasis on aldosterone.

Abstract

The metabolism of corticosteroids, especially of aldosterone, the most important mineralocorticoid, and of prednisone, a synthetic glucocorticoid, was studied in the isolated perfused liver (IPL) and in the isolated perfused kidney (IPK) of the rat. In IPL, the elimination of aldosterone at 10(-9)-10(-6) M exhibited first order kinetics. Aldosterone was converted to tetrahydroaldosterone (THA), and dihydroaldosterone (DHA) (reduced metabolites), a metabolite less polar than THA, and predominantly to more polar metabolites. These consisted of conjugated reduced metabolites, and of greater amounts of unconjugated polar metabolites. Aldosterone metabolite accumulated rapidly in the circulation. Only the polar metabolites were later excreted in the bile. The elimination of prednisone at 10(-6) M also exhibited first order kinetics, but the clearance of aldosterone was 80% higher than the clearance of prednisone, indicating that different hepatic enzymes are involved in the metabolism of these corticosteroids. In IPK, the clearance of aldosterone was only about 2% of the hepatic clearance, and amounted to 39% of the renal glomerular filtration rate. The excretory and metabolic clearance in the kidney amounted to 26% and 74%, respectively. In the combined isolated perfused liver and kidney (CIPLK) hepatic polar, both unconjugated and conjugated reduced, and less polar reduced, aldosterone metabolites accumulated in the perfusate. Only polar metabolites were excreted in bile, while all circulating metabolites were isolated from urine within 90 minutes. This indicated, that the aldosterone metabolites, which are found in the kidney are formed predominantly in the liver. The presence of the kidney in the perfusion circuit seemed to inhibit the hepatic metabolism of aldosterone, as the total clearance of aldosterone in CIPLK was 23% lower than in the single perfused liver. Furthermore, addition of aldosterone 10(-9) M to CIPLK, but not to IPK without a liver, resulted in an increasing kaliuresis in 3 subsequent periods of 30 minutes, without any concomitant antinatriuresis. The hepatic aldosterone metabolites, which were released to the perfusate in the combined experiments, thus, seemed to possess kaliuretic effect. The metabolism of aldosterone in IPL was sex dependent. In female rat liver a 75% higher clearance of aldosterone per gram of liver was found, compared to that of male rat liver obtained from rats with a similar age. And the total hepatic clearance of aldosterone was 33% higher in female rats than in younger male rats with a similar body weight. The formation of free and conjugated THA and DHA was only observed in male rat liver, while a metabolite less polar than THA was only observed in female rat liver. The predominating polar metabolites in female rat liver consisted of at least 3 polar peaks, which were neither glucuronides nor sulfates of reduced less polar aldosterone metabolites. The sex dependence of the hepatic metabolism of aldosterone was into some extend neonatally determined. Administration of a diet with a high sodium content to salt sensitive Dahl (S) rats with elevated blood pressure, resulted, in IPL, in a 28% and 35% higher clearance of aldosterone than in s rats on a normal diet, and salt resistant normotensive Dahl rats on high sodium diet, respectively. (ABSTRACT TRUNCATED)