✍ Scribed by G Sauter; F Berr; U Beuers; S Fischer; G Paumgartner
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tive pathway bypasses cholesterol 7a-hydroxylase activity. Serum concentrations of 7a-hydroxy-4-cholesten-3-Studies on rat and human hepatocytes in cell culture indicate one (a-HC) have recently been shown to reflect the activthat bile acid synthesis from 27-hydroxycholesterol might acity of cholesterol 7a-hydroxylase in humans. To evaluate count for up to 50% of the total bile acid synthesis and for the relationship between a-HC in serum and bile acid an even greater proportion of chenodeoxycholic acid (CDCA) synthesis, serum concentrations of a-HC, and rates of production. 12 Moreover, efficient conversion of 27-hydroxybile acid synthesis, as measured by the isotope dilution cholesterol to bile acids had been demonstrated both in vitro 13 technique using gas chromatography-mass spectromeand in vivo. 11 Therefore, the synthesis of total or of individual try, were determined simultaneously. Regression analybile acids may quantitatively differ considerably from the sis revealed a positive linear correlation of serum a-Hc amounts that would be expected by the measurement of hewith synthesis of cholic acid (CA) (r Å .59, P Å .02), chepatic cholesterol 7a-hydroxylase activity alone. nodeoxycholic acid (CDCA) (r Å .75, P Å .001), and total
Recently, serum concentrations of two bile acid precursors, synthesis of both primary bile acids (r Å .83, P õ .001) 7a-hydroxycholesterol and 7a-hydroxy-4-cholesten-3-one (ain patients with gallstones and normal liver function (n HC), have been proposed as indices of cholesterol 7a-hydroxy-Å 15). a-HC was also correlated to input rates of deoxylase activity in humans. Total 7a-hydroxycholesterol 14 and cholic acid (DCA) (r Å .53, P õ .05). Addition of patients free 7a-hydroxycholesterol 15 have been found to change parwith chronic cholestatic liver disease (n Å 5) improved allel with hepatic cholesterol 7a-hydroxylase activity. Morethe correlation between serum a-HC and synthesis of over, a close correlation between total 7a-hydroxycholesterol CA (r Å .75, P õ .001), CDCA (r Å .77, P õ .001), and both in serum and bile acid synthesis, as determined by the fecal primary bile acids combined (r Å .87, P õ .001). Our data balance method 16 and by the measurement of bile acid excreare in agreement with the concept that synthesis of bile tion in bile fistula patients, 17 has been found. However, the acids is regulated by cholesterol 7a-hydroxylase activity general use of this marker is limited by the need for elaborate and that a-HC in serum may serve as a convenient analytic methodology using gas chromatography-mass specmarker for the semiquantitative assessment of bile acid trometry, which is available in few laboratories. synthesis in humans. (HEPATOLOGY 1996;24:123-126.) a-HC, which is formed from 7a-hydroxycholesterol by the action of a 7a-hydroxycholesterol-specific 3b-hydroxy-C 27 -The conversion of cholesterol to bile acids is initiated by steroid dehydrogenase/isomerase in the liver, can be meathe independent actions of two different enzymes-cholessured more easily with a simple high-performance liquid terol 7a-hydroxylase or sterol 27-hydroxylase. 1,2 Cholesterol chromatography method after extraction on reversed-phase 7a-hydroxylase, which catalyzes the conversion of cholesterol silica. 18 Serum concentrations of a-HC have been reported to to 7a-hydroxycholesterol, has been identified as the rate-limchange parallel with predicted changes of bile acid synthesis iting enzyme of the major bile acid biosynthetic pathway. 3,4 in patients with bile acid malabsorption or suppression of Numerous studies in animals indicate that cholesterol 7acholesterol 7a-hydroxylase during intake of CDCA. 18,19 Morehydroxylase is under the control of a variety of factors, includover, serum concentrations of a-HC were found to be closely ing hormones, 5 dietary and newly synthesized cholesterol, 6,7 correlated to cholesterol 7a-hydroxylase activity in human and hydrophobic bile acids. 8,9 Despite its obvious clinical imliver tissue. 20,21 From these data, it has been concluded that portance, there are only limited data on the regulation of the levels of a-HC in serum reflect cholesterol 7a-hydroxylase cholesterol 7a-hydroxylase in humans. This may be explained activity in humans. 20 It remains unclear, however, whether by the methodological difficulty in determining hepatic choa-HC in serum may also serve as a semiquantitative marker lesterol 7a-hydroxylase activity and bile acid synthesis rates of bile acid synthesis rates. To study this question in more by noninvasive means.
detail, a-HC in serum (reflecting cholesterol 7a-hydroxylase The predominant role of cholesterol 7a-hydroxylase in the activity) and bile acid synthesis rates were simultaneously regulation of bile acid synthesis has recently been questioned determined by high-performance liquid chromatography 18 by the demonstration of a bile acid biosynthetic pathway initiand by the stable isotope-dilution technique employing gas ated by the 27-hydroxylation of cholesterol. 2,10,11 This alternachromatography-mass spectrometry, 22 respectively.
Abbreviations: CDCA, chenodeoxycholic acid; a-HC, 7a-hydroxy-4-cholesten-3-one; CA, Subjects. Serum concentrations of a-HC and bile acid kinetics cholic acid; DCA, deoxycholic acid.
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Evidence was recently presented that an essential part of the accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is due to acceleration of a novel pathway, involving ?a-hydroxylated intermediates in bile acid biosynthesis as precursors (J. Clin. Invest. 1986; 75:448-456). Su
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