Effect of bile acid hydroxylation on biliary protoporphyrin excretion in rat liver

The relationships between bile acid structure, protoporphyrin load, and biliary protoporphyrin excretion were studied in rat livers perfused with 0 or 0.7 mumol/min taurocholate and protoporphyrin loads between 350 and 35,525 nmol. Bile acid treatment increased the excretion of extracted protoporphyrin from 0.4 to 28%, the maximal biliary protoporphyrin concentration 32-fold, the protoporphyrin excretion rate approximately 150-fold, and the coupling of excreted protoporphyrin to bile acid. Infusions (0.7 mumol/min) of bile acids differing in structure with 1,500 nmol protoporphyrin all significantly increased protoporphyrin excretion but ursodeoxycholate and tauroursodeoxycholate did so less than others. Infusions (0.175-1.4 mumol/min) of taurocholate, deoxycholate, ursodeoxycholate, and chenodeoxycholate confirmed that protoporphyrin excretion increased significantly more with taurocholate or deoxycholate than chenodeoxycholate and chenodeoxycholate more than ursodeoxycholate. The relative ineffectiveness of dihydroxylated bile acids with a hydroxy group at the seven position (alpha- or beta-configuration) was not correlated with physicochemical parameters of the bile acids and remains unexplained. The findings suggest that ursodeoxycholate is the least acceptable bile acid to consider as a potential treatment for protoporphyria.

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Mechanism of bile acid facilitation of biliary protoporphyrin excretion in rat liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.268.5.g754 ◽

1995 ◽

Vol 268 (5) ◽

pp. G754-G763 ◽

Cited By ~ 1

Author(s):

M. M. Berenson ◽

M. Y. el-Mir ◽

L. K. Zhang

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Intracellular Transport ◽

Organic Anion ◽

Anion Transport ◽

Organic Anion Transport ◽

Canalicular Membrane ◽

Rat Livers ◽

Eisai Hyperbilirubinemic Rat

The mechanism(s) by which bile acids increase biliary protoporphyrin excretion was characterized using perfused rat livers. We determined 1) relationships between biliary bile acids, phospholipid, and protoporphyrin, using rapid kinetic analyses; 2) protoporphyrin excretion in livers with defective canalicular multispecific organic anion transport; 3) effects of intracellular vesicular transport inhibition with colchicine and monensin; and 4) the role of luminal bile acids, using retrograde intrabiliary taurocholate injections. Biliary protoporphyrin excretion peaked with phospholipid excretion 14-18 min after loading. Protoporphyrin excretion induced by taurocholate was not related to effects on intracellular transport, including colchicine- and monensin-inhibitable vesicular systems. Eisai hyperbilirubinemic rat livers excreted protoporphyrin similarly to controls. Retrograde intrabiliary taurocholate injections increased protoporphyrin output. Collectively, these data suggest that 1) intracellular protoporphyrin transport is mediated by nonvesicular carriers targeted to the canalicular membrane, and 2) bile acid facilitates protoporphyrin translocation into bile in the same manner it effects phospholipid excretion.

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The role of conjugation reactions in enhancing biliary secretion of bile acids

Biochemical Journal ◽

10.1042/bj2140923 ◽

1983 ◽

Vol 214 (3) ◽

pp. 923-927 ◽

Cited By ~ 36

Author(s):

D A Vessey ◽

J Whitney ◽

J L Gollan

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Hepatic Uptake ◽

Biliary Secretion ◽

Side Chain ◽

Isolated Perfused Rat Liver ◽

Rat Livers ◽

Kinetics Of ◽

Methylene Group

Shortening the five-carbon carboxylic acid side chain of cholic acid by one methylene group gave rise to a bile acid (norcholate) that was not a substrate for the bile acid-conjugating enzymes. The metabolism and biliary secretion of norcholate in intact liver was examined in the isolated perfused rat liver system. When rat livers were perfused with 14-20 microM solutions of norcholate for 10 min, norcholate was found in the unconjugated form in liver, venous effluent and bile. Neither tauronorcholate nor glyconorcholate was detectable by high-pressure liquid chromatography or fast-atom-bombardment mass spectrometry. The kinetics of hepatic uptake and biliary secretion of norcholate was compared with that for cholate, taurocholate and chemically synthesized tauronorcholate. The latter three bile acids were completely cleared from the perfusate and efficiently secreted into the bile. However, norcholate was incompletely extracted from the perfusate, and this was shown to be at least partially due to its relatively lower rate of hepatic uptake. Furthermore, the rate of norcholate secretion into bile was greatly reduced relative to the secretion of cholate or chemically synthesized tauronorcholate, even though the concentration of norcholate in the liver was comparatively high. These data demonstrate that the conjugation of bile acids greatly facilitates their secretion into bile.

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Amiloride and taurine inhibit cholate-induced HCO3(-)-rich choleresis in perfused rat livers

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.259.3.g453 ◽

1990 ◽

Vol 259 (3) ◽

pp. G453-G461

Author(s):

M. S. Anwer ◽

J. M. Atkinson ◽

P. Zimniak

Keyword(s):

Bile Acid ◽

Biliary Excretion ◽

Bile Flow ◽

Excretion Rate ◽

Isolated Hepatocytes ◽

Hepatic Uptake ◽

Polar Compound ◽

Biliary Reabsorption ◽

Rat Livers ◽

Primary Activation

Bile acid-induced HCO3(-)-rich choleresis may be due to primary activation of sinusoidal Na(+)-H+ exchange or to biliary reabsorption of unconjugated bile acid. To test these hypotheses, we studied the effect of cholate and taurocholate (TC) (infused at 10 mumol/min for 20 min) on net H+ efflux, biliary [HCO3-], and bile flow in perfused rat livers and on intracellular pH (pHi) in isolated hepatocytes. Cholate, but not TC, produced HCO3(-)-rich choleresis. Amiloride and taurine decreased cholate-induced choleresis and HCO3- excretion and biliary excretion of unconjugated cholate. Amiloride, but not taurine, decreased cholate-induced net H+ efflux. Both cholate and TC (200-750 microM) decreased pHi. Cholate was metabolized to a polar compound, most likely cholate glucuronide, in the presence of amiloride. These results are consistent with the hypothesis that the biliary reabsorption of unconjugated cholate may be involved in HCO3(-)-rich choleresis. Amiloride also inhibited net hepatic uptake and biliary excretion of cholate and TC without affecting hepatic content of bile acids. It is suggested that amiloride may decrease the maximal excretion rate of cholate and TC. Since cholate and TC induce amiloride-sensitive net H+ efflux and decrease pHi, it appears that cholate and TC activate Na(+)-H+ exchange indirectly by decreasing pHi.

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Activation of protein kinase C alpha and delta by bile acids: correlation with bile acid structure and diacylglycerol formation

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)30029-8 ◽

1997 ◽

Vol 38 (12) ◽

pp. 2446-2454 ◽

Cited By ~ 2

Author(s):

Y P Rao ◽

R T Stravitz ◽

Z R Vlahcevic ◽

E C Gurley ◽

J J Sando ◽

...

Keyword(s):

Protein Kinase C ◽

Bile Acid ◽

Protein Kinase ◽

Bile Acids ◽

Kinase C ◽

Protein Kinase C Alpha ◽

Acid Structure

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Influence of bile acid structure on bile flow and biliary lipid secretion in the hamster

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1984.247.6.g736 ◽

1984 ◽

Vol 247 (6) ◽

pp. G736-G748 ◽

Cited By ~ 6

Author(s):

D. Gurantz ◽

A. F. Hofmann

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Bile Flow ◽

Enterohepatic Circulation ◽

Acid Output ◽

Chain Structure ◽

Side Chain ◽

Biliary Lipid ◽

Lipid Secretion ◽

Acid Structure

A comprehensive study of the influence of bile acid structure on bile flow and biliary lipid secretion was carried out by infusing pure bile acids at a physiological rate into the proximal small intestine of a bile fistula hamster. Twelve individual bile acids, cholate (C), ursocholate (UC), chenodeoxycholate (CDC), and ursodeoxycholate (UDC) as their glycine (G), taurine (T), or unconjugated form, were studied so that influence of the hydroxy substituents as well as side-chain structure could be defined. The pattern of bile acid output was dependent on bile acid structure and reflected the site and rate of intestinal absorption. Conjugated bile acid output was delayed because of late ileal absorption, and TUC was poorly absorbed. Unconjugated trihydroxy bile acids, C and UC, also exhibited a delay in absorption, while CDC and UDC were absorbed immediately and achieved the highest bile acid output. Unconjugated bile acids were conjugated initially mostly with taurine and then mostly with glycine. The effect of glycine conjugates of each bile acid on bile flow and biliary lipid secretion was similar to that of their corresponding taurine conjugates. All conjugated bile acids induced a similar rate of bile flow (9–15 microliter bile/mumol bile acid), but unconjugated bile acids other than C induced more flow (20–25 microliter bile/mumol bile acid) than their corresponding conjugates. Conjugates of the dihydroxy bile acids induced a greater secretion of phospholipid and cholesterol than cholyl conjugates, whereas conjugates of UC were unique in inducing extremely low phospholipid and cholesterol secretion. For an increase of 1 mumol X min-1 X kg-1 in bile acid output, the increase in phospholipid secretion was 0.072 mumol X min X kg for GCDC and TCDC; 0.051 mumol X min-1 X kg-1 for GUDC and TUDC; and 0.030 mumol X min-1 X kg-1 for GC and TC. Increase in cholesterol output per mumol X min-1 X kg-1 of bile acid output was 0.013 mumol X min-1 X kg-1 for GCDC and TCDC, 0.011 mumol X min-1 X kg-1 for GUDC and TUDC, and 0.005 mumol X min-1 X kg-1 for GC and TC. In general, unconjugated bile acids induced more phospholipid and cholesterol than their corresponding conjugates; however, the rank-order effect of the steroid nucleus substituents was similar to that observed for the respective conjugates. These results indicate that both nuclear and side-chain structure influence the enterohepatic circulation and biliary secretory properties of bile acids.(ABSTRACT TRUNCATED AT 400 WORDS)

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Modulation of hepatic biotransformation and biliary excretion of bile acid by age and sinusoidal bile acid load

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1987.252.1.g114 ◽

1987 ◽

Vol 252 (1) ◽

pp. G114-G119 ◽

Cited By ~ 1

Author(s):

U. Baumgartner ◽

K. Miyai ◽

W. G. Hardison

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Residence Time ◽

Biliary Excretion ◽

Bile Acid Concentration ◽

Acid Processing ◽

Acid Load ◽

The Difference ◽

Rat Livers ◽

Hepatic Biotransformation

Pericentral hepatocytes excrete bile acids more slowly and biotransform them more than periportal cells. This may reflect adaptation to low pericentral bile acid concentration or may be intrinsic. We studied two models in which pericentral bile acid concentrations are high: the 72-h choledocho-caval shunt (CCS) rat and the 3- to 4-wk-old rat. Livers were perfused forward or backward to assess periportal or pericentral hepatocyte function. Taurodeoxycholate (TDC) was infused at 32 nmol X min-1 X g liver-1, and a bolus of [3H]TDC was given to assess metabolism and excretion of bile acids. In CCS livers perfused backward, pericentral cells resembled periportal cells of controls in that time to excrete 50% of administered [3H]TDC (t50) was reduced by two-thirds and [3H]TDC biotransformation was reduced by about half. In young livers t50 was half that of adult livers when perfused backward. Biotransformation, however, was not reduced. Young livers biotransformed more than adult controls for any given residence time of bile acid in the liver. We conclude that the difference between pericentral and periportal cells as regards bile acid processing is adaptive. Livers from young rats biotransform more bile acid than those from controls under similar conditions.

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Formation of Hyodeoxycholic Acid from Muricholic Acid and Hyocholic Acid by an Unidentified Gram-Positive Rod Termed HDCA-1 Isolated from Rat Intestinal Microflora

Applied and Environmental Microbiology ◽

10.1128/aem.65.7.3158-3163.1999 ◽

1999 ◽

Vol 65 (7) ◽

pp. 3158-3163 ◽

Cited By ~ 43

Author(s):

H. J. Eyssen ◽

G. De Pauw ◽

J. Van Eldere

Keyword(s):

Bile Acid ◽

Growth Factor ◽

Bile Acids ◽

Hydroxy Group ◽

Intestinal Microflora ◽

Culture Medium ◽

Gram Positive ◽

Hyodeoxycholic Acid ◽

Hyocholic Acid ◽

Germfree Rats

ABSTRACT From the rat intestinal microflora we isolated a gram-positive rod, termed HDCA-1, that is a member of a not previously described genomic species and that is able to transform the 3α,6β,7β-trihydroxy bile acid β-muricholic acid into hyodeoxycholic acid (3α,6α-dihydroxy acid) by dehydroxylation of the 7β-hydroxy group and epimerization of the 6β-hydroxy group into a 6α-hydroxy group. Other bile acids that were also transformed into hyodeoxycholic acid were hyocholic acid (3α,6α,7α-trihydroxy acid), α-muricholic acid (3α,6β,7α-trihydroxy acid), and ω-muricholic acid (3α,6α,7β-trihydroxy acid). The strain HDCA-1 could not be grown unless a nonconjugated 7-hydroxylated bile acid and an unidentified growth factor produced by a Ruminococcus productus strain that was also isolated from the intestinal microflora were added to the culture medium. Germfree rats selectively associated with the strain HDCA-1 plus a bile acid-deconjugating strain and the growth factor-producing R. productus strain converted β-muricholic acid almost completely into hyodeoxycholic acid.

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Bile acid structure and biliary lipid secretion. II. A comparison of three hydroxy and two keto bile acids.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1978.234.6.e637 ◽

1978 ◽

Vol 234 (6) ◽

pp. E637

Author(s):

N E Hoffman ◽

R B Sewell ◽

R A Smallwood

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Biliary Lipid ◽

Lipid Secretion ◽

Dihydroxy Acid ◽

Intracellular Effect ◽

The Difference ◽

Acid Structure ◽

Cholanoic Acid ◽

Anesthetized Cat

The effect of five bile acids on biliary lipid secretion was studied in the pentobarbital-anesthetized cat. The dihydroxy acid, taurohyodeoxycholic acid, was indistinguishable from another dihydroxy acid, taurochenodeoxycholic acid, but secretion of both phospholipid and cholesterol was considerably reduced with two mono-keto dihydroxy acids, tauro-3alpha,12alpha-dihydroxy-7-keto-5beta-cholanoic acid and tauro-3alpha,7alpha-dihydroxy-12-keto-5beta-cholanoic acid. The effect of a trihydroxy bile acid, taurocholic acid was as previously described. The effect of the keto bile acids may be explained by the ability of these bile acids to solubilize lipid, but such an explanation is inadequate for the difference between di- and trihydroxy bile acids. An intracellular effect of bile acid is postulated.

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