Dietary phytosterols are cholesterol-lowering agents that interfere with the intestinal absorption of cholesterol. In the present study, we have studied their effects on cholesterol biosynthesis in human cells, particularly in the sterol-conversion pathway. For this, both Caco-2 (intestinal mucosa) and HL-60 (promyelocytic) human cell lines were incubated with [14C]acetate, and the incorporation of radioactivity into sterols was determined using HPLC and radioactivity detection online. Sterols containing a double bond at C-22 in the side chain (stigmasterol, brassicasterol and ergosterol) dramatically inhibited the activity of sterol Δ24-reductase, as indicated by the decrease in radioactivity incorporation into cholesterol and the accumulation of its precursors (mainly desmosterol). Phytosterols with the saturated side chain (β-sitosterol and campesterol) were inactive in this regard. The inhibition of sterol 24-reductase was confirmed in rat liver microsomes by using 14C-labelled desmosterol as the substrate. The 22-unsaturated phytosterols acted as competitive inhibitors of sterol 24-reductase, with Ki values (41.1, 42.7 and 36.8μM for stigmasterol, brassicasterol and ergosterol respectively) similar to the estimated Km for desmosterol (26.3μM). The sterol 5,22-cholestedien-3β-ol, an unusual desmosterol isomer that lacks the alkyl groups characteristic of phytosterols, acted as a much stronger inhibitor of 24-reductase (Ki = 3.34μM). The usually low intracellular concentrations of the physiological substrates of 24-reductase explains the strong inhibition of cholesterol biosynthesis that these compounds exert in cells. Given that inhibition of sterol 24-reductase was achieved at physiologically relevant concentrations, it may represent an additional mechanism for the cholesterol-lowering action of phytosterols, and opens up the possibility of using certain 22-unsaturated sterols as effective hypocholesterolaemic agents.

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