Abstract
In patients with cerebrotendinous xanthomatosis (CTX), diminished cholic acid production is associated with incomplete oxidation of the cholesterol side chain and the excretion of C(25)-hydroxy bile alcohols. The aims of this investigation were 1) to provide quantitative information on the pool size and production rate of chenodeoxycholic acid by the isotope dilution technique; and 2) to investigate the possible existence of a block in chenodeoxycholic acid synthesis and explain the absence of chenodeoxycholic acid precursors in CTX. After the injection of [24-(14)C]chenodeoxycholic acid, measurements of chenodeoxycholic acid pool size and production rate in a CTX subject were, respectively, 1/20 and 1/6 as great as controls. Further, three potential precursors of chenodeoxycholic acid, namely [G-(3)H]7alpha-hydroxy-4-cholesten-3-one, [G-(3)H]5beta-cholestane-3alpha,7alpha,25-triol, and [G-(3)H]5beta-cholestane-3alpha,7alpha,26-triol, were administered to the CTX and control subjects and the specific activity curves of [G-(3)H]cholic acid and [G-(3)H]chenodeoxycholic acid were constructed and compared. In the control subjects, the two bile acids decayed exponentially, but in the CTX patient maximum specific activities were abnormally delayed, indicating the hindered transformation of precursor into bile acid. These results show that chenodeoxycholic acid synthesis is small in CTX and that the conversion of 7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestane-3alpha,7alpha,25-triol, and 5beta-cholestane-3alpha,7alpha,26-triol to both chenodeoxycholic acid and cholic acid were similarly impaired.
Highlights
Our results showed that chenodeoxycholic acid synthesis was defective in CTX subjects, andthat this abnormality was associated with an impaired oxidation of both the 25- and 26-hydroxylated cholestanetriols
Mass and radioactivityof cholic acid and chenodeoxycholic acid were determined by a combination of thin-layer chromatography (TLC), gas-liquid chromatography (GLC), and liquid scintillation counting
Cholic Acid mg dpm Chenodeoxycholic acid mg dpm Patients were pulse labeled by intravenous injection of 3 pCi of 5P-[G-3H]cholestane-3a,7a,26-triolM.ass and radioactivity of cholic acid and chenodeoxycholic acid were determined by a combination of TLC, GLC, and liquid scintillation counting
Summary
Studies were conducted in five patients who were hospitalized at theEast Orange VeteransAdministration Hospital. E This patient subsequently received [2,4-3H]cholicacid (25 pCi) + [ 2 4 - " C ] chenod ~ ~ ~ a~c~idh(~6I.7i ~pci) to determine bile acid kinetics (see Table 2). The bile acids were applied to 20 x 20-cm TLC acidwereisolated from these specimens andthe plates (silica geGl , 0.25 mm thicka)long with reference specific activity of each bile acidwas determined and standards of cholic acid and chenodeoxycholic acid. Cholic bile alcohols into both cholicacid and chenodeoxyacid ( R ,0.12), deoxycholic acid( R , 0.35), and cheno- cholicacid in CTX, 3pCi of5/3-[G-3H]cholestanedeoxycholic acid( R ,0.40) wereeluted with methanol 3a,7a,26-triol and 1 pCi of 5j3-[24-14C]cholestane-3a, after visualizingthe bands with Izvapor. C ) The pool sizeand production rate of cholic acid with three 20-ml portions of ethyl ether-benzene 2: 1 and chenodeoxycholic acid were determined in sub-. Calculations of pool size and production rates were made by the isotope dilution technique according to Lindstedt (12)
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