Summary
Bile acid profiles from plasma and urine of six patients suffering from intrahepatic cholestasis were studied before and during treatment with phenobarbital. All patients responded to this treatment by decreasing their plasma bile acid levels. Using gas chromatographic and mass spectrometric methods for separation and identification of the bile acids, especially the occurrence of major atypical bile acids was quantitatively evaluated.
The plasma bile acid lowering effect of phenobarbital in intrahepatic cholestasis can be partly explained by an increased formation of tetrahydroxylated bile acids, which are rapidly excreted by renal pathways. These tetrahydroxylated bile acids, present as nonsulfated compounds, have high renal excretory flow rates exceeding those of bile acid sulfates. Their enterohepatic circulation, however, seems to be low, since only small amounts of tetrahydroxylated bile acids can be found in bile. It is mainly the 1- and 6-hydroxylation that is stimulated by phenobarbital. The exact site of formation of tetrahydroxylated bile acids, however, is still unknown. These findings may provide a rationale for the institution of a phenobarbital treatment in cases of intrahepatic cholestasis.
Zusammenfassung
Bei sechs Patienten mit intrahepatischer Cholestase wurden Gallensäurenprofile in Plasma und Urin vor und während einer Behandlung mit Phenobarbital untersucht. Alle Patienten sprachen auf diese Therapie mit einer Senkung der Plasmagallensäurenspiegel an. Unter Einsatz gaschromatografischer und massenspektrometrischer Methoden wurde besonders das Vorkommen atypischer Gallensäuren quantitativ zu erfassen versucht.
Bei Berücksichtigung des Vorkommens atypischer Gallensäuren kann der Effekt des Phenobarbitals auf eine verstärkte Bildung tetrahydroxylierter Gallensäuren, welche rasch über die Nieren ausgeschieden werden, zurückgeführt werden. Diese tetrahydroxylierten Gallensäuren, welche im Urin als nicht sulfatveresterte Substanzen vorliegen, zeigen höhere renale exkretorische Durchflußgeschwindigkeiten als Gallensäurensulfate. Dagegen scheint ihre enterohepatische Zirkulation geringfügig zu sein, da nur geringe Anteile an der Gallensäurenfraktion der Galle gefunden werden.
Phenobarbital stimuliert hauptsächlich die 1- und 6-Hydroxylierung. Der Ort der Bildung der tetrahydroxylierten Gallensäuren kann jedoch noch nicht sicher festgelegt werden. Die vorliegenden Befunde lassen den Einsatz von Phenobarbital bei Vorliegen von intrahepatischen Cholestasen als sinnvoll erscheinen.
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References
Almé B, Bremmelgaard A, Sjövall J, Thomassen P (1976) Unusual bile acids in human urine characterized by a new analytical method. In: Preisig R, Bircher J, Paumgartner G (eds) The Liver. Quantitative aspects of structure and function. Editio Cantor, Aulendorf, pp 227–235
Almé B, Bremmelgaard A, Sjövall J, Thomassen P (1977) Analysis of metabolic profiles of bile acids in urine using a lipophilic anion exchanger and computerized gas — liquid chromatography mass spectrometry. J Lipid Res 18:339–362
Almé B, Sjövall J (1980) Analysis of bile acid glucuronides in urine. Identification of 3α, 6α, 12α-trihydroxy-5β-cholanoic acid. J Steroid Biochem 13:907–916
Back P, Gerok W (1977) Differences in renal excretion between glyco-, tauroconjugates, sulfoconjugates and glucuronoconjugates of bile acids in cholestasis. In: Paumgartner G, Stiehl A (eds) Bile acid metabolism in health and disease. MTP Press, Lancaster, pp 93–100
Back P, Gerok W (1978) Zum Effekt des Phenobarbitals bei intrahepatischer Cholestase. Stimulierung der Gallensäuren — 6α-Hydroxylierung. Inn Med 5:329–336
Back P, Walter K (1980) Developmental pattern of bile acid metabolism as revealed by bile acid analysis of meconium. Gastroenterology 78:671–676
Back P (1981) Klinische Bedeutung der Bestimmung atypischer Gallensäuren. Lab Med 5:123–128
Berthelot P, Erlinger S, Dhumeaux D, Preaux AM (1970) Mechanism of phenobarbital-induced hypercholeresis in the rat. Am J Physiol 219:809–813
Black M, Perrret RD, Carter AE (1973) Hepatic bilirubin UDP-glucuronyl transferase activity and cytochrome P 450 content in a surgical population, and the effects of preoperative drug therapy. J Lab Clin Med 81:704–712
Bremmelgaard A, Sjövall J (1979) Bile acid profiles in urine of patients with liver disease. Eur J Clin Invest 9:341–348
Bremmelgaard A, Sjövall J (1980) Hydroxylation of cholic, chenodeoxycholic, and deoxycholic acids in patients with intrahepatic cholestasis. J Lipid Res 21:1072–1081
Cronholm T, Makino I, Sjövall J (1972) Steroid metabolism in rats given (1-2H2) ethanol. Oxidoreduction of isomeric 3-hydroxycholanoic acids and reduction of 3-oxo-4-cholenoic acid. Eur J Biochem 26:251–258
Einarsson K, Johannson G (1968) Effect of phenobarbital on the conversion of cholesterol to taurocholic acid. Eur J Biochem 6:293–298
Einarsson K, Johannson G (1969) Effect of carbon monoxide and phenobarbital on hydroxylation of bile acids by rat liver microsomes. FEBS Lett 4:177–180
Elliott WH (1980) Mass spectra of bile acids. In: Waller GR, Dermer OC (eds) Biochemical applications of mass spectrometry, 1st suppl vol. Wiley, New York Chichester Brisbane Toronto, pp 229–253
Eneroth P (1963) Thin layer chromatography of bile acids. J Lipid Res 4:11–16
Fröhling W, Stiehl A, Czygan P, Liersch M, Kommerell, B, Rotthauwe HW, Becker M (1977) Induction of bile acid glucuronide formation in children with intrahepatic cholestasis. In: Paumgartner G, Stiehl A (eds) Bile acid metabolism in health and disease. MTP Press, Lancaster, pp 101–104
Fyffe J, Dutton GJ (1975) Induction of UDP-glucose dehydrogenase during development, organ culture, and exposure to phenobarbital. Its relation to levels of UDP-glucuronic acid and overall glucuronidation in chicken and mouse. Biochim Biophys Acta 411:41–49
Ginsberg RL, Garnick MB (1977) Effect of phenobarbital on biliary lipid metabolism in normal man. Gastroenterology 72:1221–1227
Greim H, Trülzsch D, Czygan P, Rudick J, Hutterer F, Schaffner F, Popper H (1972) Mechanism of cholestasis. 6. Bile acids in human livers with or without biliary obstruction. Gastroenterology 63:846–850
Makino I, Sjövall J (1972) A versatile method for analysis of bile acids in plasma. Anal Lett 5:341–349
Makita M, Wells WW (1963) Quantitative analysis of fecal bile acids by gas-liquid chromatography. Anal Biochem 5:523–530
Ohnhaus EE, Thorgeirsson S, Davies DS, Beckenridge A (1971) Changes in liver blood flow during enzyme induction. Biochem Pharmacol 20:2561–2570
Ostrower VS, Coan P, Kern F jr (1977) Effect of phenobarbital on intestinal cholic acid absorption in the rat. Gastroenterology 67:1162–1168
Redinger RN, Small DM (1973) Primate biliary physiology. VIII. The effect of phenobarbital upon bile salt synthesis and pool size, biliary lipid secretion, and bile composition. J Clin Invest 52:161–172
Reys H, Levi AJ, Gatmaitan Z, Arias IM (1971) Studies of Y and Z, two hepatic cytoplasmic organic anion binding proteins: effect of drugs, chemicals, hormones, and cholestasis. J Clin Invest 50:2242–2258
Schneider JJ, Bhacca NS (1966) 1β-Hydroxylation of 3α, 17α, 20β, 21-tetrahydroxy-5β-pregnan-11-one and of other 5β-steroids in a man and by surviving liver slices of the guinea pig. J Biol Chem 241:5313–5324
Sharp HL, Mirkin BL (1972) Effect of phenobarbital on hyperbilirubinemia, bile acid metabolism, and microsomal enzyme activity in chronic intrahepatic cholestasis of childhood. J Pediatr 81:116–126
Stiehl A, Thaler MM, Admirand WH (1972) The effect of phenobarbital on bile salts and bilirubin in patients with intrahepatic and extrahepatic cholestasis. N Engl J Med 286:858–861
Stiehl A, Thaler MM, Admirand WH (1973) Effects of phenobarbital on bile salts and bilirubin in patients with intrahepatic bile duct hypoplasia. Pediatrics 51:992–997
Stiehl A, Becker M, Czygan P, Fröhling W, Kommerell B, Rotthauwe HW (1980) Bile acids and their sulphated and glucuronidated derivatives in bile, plasma, and urine of children with intrahepatic cholestasis: effects of phenobarbital treatment. Eur J Clin Invest 10:307–316
Trülzsch D, Roboz J, Greim H, Czygan P, Rudick J, Hutterer F, Schaffner F, Popper H (1974) Hydroxylation of taurolithocholate by isolated human liver microsomes. Biochem Med 9:158–166
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Dedicated to Prof. Dr. G. W. Löhr on his 60th birthday
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Back, P. Phenobarbital-induced alterations of bile acid metabolism in cases of intrahepatic cholestasis. Klin Wochenschr 60, 541–549 (1982). https://doi.org/10.1007/BF01724209
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DOI: https://doi.org/10.1007/BF01724209