Abstract
The metabolism of mevalonic acid by both sterol and non-sterol pathways has been evaluated in nine tissues of the rat. An in vitro estimation of the non-sterol, or "shunt", pathway of mevalonate metabolism was made possible by determining the conversion of [2-14C]mevalonate or [5-14C]mevalonate to 14CO2 in tissue slices. In confirmation of our previous results, the kidney was found to play a major role in the metabolism of mevalonate to sterols and sterol precursors. The shunt pathway accounted for a significant percentage of the mevalonate metabolized in kidney, ileum, spleen, lung and testes, but was of minor importance or undetectable in liver, brain, skin, and adipose tissue. Kidney, however, proved to be by far the most active tissue site of mevalonate metabolism by the shunt mechanism in that, on an average, renal tissue metabolized (R)-[14C]mevalonate over the non-sterol pathway at a rate that was 21 times that of any other tissue examined. These results indicate that the kidneys are of major importance in the metabolism of mevalonate by each of the known pathways of metabolism of this sterol precursor.
Highlights
Popjak’s findings of shunt activity in these two tissues [3] when assayed in uiuo
In our previous studies it was demonstrated that within the kidney the cortex represents the major site of mevalonate metabolism to squalene and sterols; and, the glomeruli of the renal cortex were shown to be responsible for over 95% of the mevalonate metabolized by this pathway
1 In studies completed after preparation of this manuscript, we have found that even in 13-day-old rats the kidney is the major site of mevalonate shunt activity: no significant oxidation of
Summary
Animals and Incubation Procedures-MaleSprague-Dawley rats weighing between 150 and 250 g were used throughout these studies.They were maintained on Purina rat chow and water ad libitum.Animals were anesthetized with ether and decapitated, and the organs to be studied were rapidly removed and placed in chilled Krebs-bicarbonate buffer. Sprague-Dawley rats weighing between 150 and 250 g were used throughout these studies. They were maintained on Purina rat chow and water ad libitum. Animals were anesthetized with ether and decapitated, and the organs to be studied were rapidly removed and placed in chilled Krebs-bicarbonate buffer. Slices of each tissue (0.5 mm thick) were prepared with a McIlwain tissue slicer. 200 mg of slices from each tissue were placed in 25-ml centerwell flasks containing 2 ml of Krebs-Ringer bicarbonate buffer and 1 PCi (209 nmol) of (R, S)- [2-‘“Clmevalonate as the potassium salt, specific activity 18 mCi/. Mm (Amersham Biochemical Centre), or (R,S)- [5-“Clmevalonate, specific activity 13 mCi/mmol (Schwarz/Mann). All experiments were carried out in duplicate, and the individual figures in each case represent the averages of these two values
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