From Cholestanol and Cholesterol

The relationship of cholesterol to cholestanol has now been delineated. Early experiments of Schoenheimer ef al. (103, 104) and Rosenfeld and Webster (105) resulted in a proposal that cholesterol was metabolized to -cholestenone (XXIX), which was reduced to cholestanol or coprostanol (106) indeed. Baker and Greenberg (106) detected C-cholestanol in rat feces after administration of radioactive acetate. Anker and Bloch (107) and Stokes et al. (108) found efficient conversion of labeled J -cholestenone to tissue cholestanol in rats. Cholesterol was shown (109) to be a precursor of cholestanol in the adrenals, liver, and intestine of guinea pigs. With cholesterol-4- - C-4/3- H Werbin et al. showed that the cholestanol isolated from the adrenals contained as much as 14% of the tritium at positions 5 and 6, whereas the cholestanol obtained from liver and intestine was virtually devoid of tritium at these positions (110). Based on these observations they proposed the following possible pathway  

A -Cholestadiene-3-one Support for a ketonic intermediate in this conversion was provided by Rosenfeld et al. (Ill, 112) who showed that cholestanol obtained from plasma, red 

Mosbach and colleagues have contributed extensively to a better understanding of the mechanism of biosynthesis of cholestanol. After intracardial administration of mevalonate- C to guinea pigs, radioactive cholestanol was isolated from liver, intestinal wall, and adrenals (117). With rat liver homogenates the incorporation of C-mevalonate or C-cholesteroI into C-cholestanol of the order of 0.05% in 4 hr (118).t The 5a-reductase of rat liver and adrenal localized (119) in the microsomal fraction, was shown to require NADPH, exhibited product inhibition, and was more active in preparations from female than male rats. The enzyme was considered distinct from the Cjg- and C2i-5a reductases, since it was inhibited by Cjg-3-keto-/I steroids. 

The 3 hydroxysteroid reductase of rat liver which catalyzes the conversion of XXX to cholestanol (XXXI) was localized also in the microsomal fractions, and shown to provide the epimeric alcohols in a ratio of 10 1 (3/3 3a) in the presence of NADPH. The enzyme was not inhibited by cholestanol, but pronounced inhibition was noted with 7-keto- or 7a-hydroxycholestanoI (XXXII) or zl -cholestenone (XXVIII) (120). This enzyme differs from the Cj9 steroid reductase, since the latter utilize NADH equally well and provides predominantly the 3a-ol. 

The origin of alio bile acids from cholestanol is clearly established (121, 36,28,122,40,123). After separation of two unidentified biliary acids similar to, but not identical with, cholic and chenodeoxycholic acids, Harold et al. 

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