The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
K Wikvall - One of the best experts on this subject based on the ideXlab platform.
-
Gene structure of pig sterol 12α-hydroxylase (CYP8B1) and expression in fetal liver: comparison with expression of Taurochenodeoxycholic Acid 6α-hydroxylase (CYP4A21)
Biochimica et biophysica acta, 2003Co-Authors: Kerstin Lundell, K WikvallAbstract:Cholic Acid is the major trihydroxy bile Acid formed in most mammals. The domestic pig (Sus scrofa) is an exception. The bile of adult pig is devoid of cholic Acid whereas hyocholic Acid is found in amounts equal to that of cholic Acid in humans. The pathway leading to formation of hyocholic Acid is believed to be species-specific and to have evolved in the pig to compensate for a nonexistent or deficient cholic Acid biosynthesis. However, a high level of cholic Acid has recently been found in the bile of fetal pig. Here we describe that a gene encoding the key enzyme in cholic Acid biosynthesis, the sterol 12alpha-hydroxylase (CYP8B1), is in fact present in the pig genome. The deduced amino Acid sequence shows 81% identity to the human and rabbit orthologues. CYP8B1 mRNA is expressed at significant levels in fetal pig liver. Both CYP8B1 and the key enzyme in hyocholic Acid formation, Taurochenodeoxycholic Acid 6alpha-hydroxylase (CYP4A21), were found to be expressed in pig liver in a developmental-dependent but opposite fashion.
-
Cloning and Expression of a Pig Liver Taurochenodeoxycholic Acid 6α-Hydroxylase (CYP4A21) A NOVEL MEMBER OF THE CYP4A SUBFAMILY
The Journal of biological chemistry, 2000Co-Authors: Kerstin Lundell, Ronnie Hansson, K WikvallAbstract:Abstract A cytochrome P450 expressed in pig liver was cloned by polymerase chain reaction using oligonucleotide primers based on amino Acid sequences of the purified Taurochenodeoxycholic Acid 6α-hydroxylase. This enzyme catalyzes a 6α-hydroxylation of chenodeoxycholic Acid, and the product hyocholic Acid is considered to be a primary bile Acid specific for the pig. The cDNA encodes a protein of 504 amino Acids. The primary structure of the porcine Taurochenodeoxycholic Acid 6α-hydroxylase, designated CYP4A21, shows about 75% identity with known members of the CYP4A subfamily in rabbit and man. Transfection of the cDNA for CYP4A21 into COS cells resulted in the synthesis of an enzyme that was recognized by antibodies raised against the purified pig liver enzyme and catalyzed 6α-hydroxylation of Taurochenodeoxycholic Acid. The hitherto known CYP4A enzymes catalyze hydroxylation of fatty Acids and prostaglandins and have frequently been referred to as fatty Acid hydroxylases. A change in substrate specificity from fatty Acids or prostaglandins to a steroid nucleus among CYP4A enzymes is notable. The results of mutagenesis experiments indicate that three amino Acid substitutions in a region around position 315 which is highly conserved in all previously known CYP4A and CYP4B enzymes could be involved in the altered catalytic activity of CYP4A21.
-
6α-Hydroxylation of Taurochenodeoxycholic Acid and lithocholic Acid by CYP3A4 in human liver microsomes
Biochimica et biophysica acta, 1999Co-Authors: Z Araya, K WikvallAbstract:The aim of the present study was to identify the enzymes in human liver catalyzing hydroxylations of bile Acids. Fourteen recombinant expressed cytochrome P450 (CYP) enzymes, human liver microsomes from different donors, and selective cytochrome P450 inhibitors were used to study the hydroxylation of Taurochenodeoxycholic Acid and lithocholic Acid. Recombinant expressed CYP3A4 was the only enzyme that was active towards these bile Acids and the enzyme catalyzed an efficient 6alpha-hydroxylation of both Taurochenodeoxycholic Acid and lithocholic Acid. The Vmax for 6alpha-hydroxylation of Taurochenodeoxycholic Acid by CYP3A4 was 18.2 nmol/nmol P450/min and the apparent Km was 90 microM. Cytochrome b5 was required for maximal activity. Human liver microsomes from 10 different donors, in which different P450 marker activities had been determined, were separately incubated with Taurochenodeoxycholic Acid and lithocholic Acid. A strong correlation was found between 6alpha-hydroxylation of Taurochenodeoxycholic Acid, CYP3A levels (r2=0.97) and testosterone 6beta-hydroxylation (r2=0.9). There was also a strong correlation between 6alpha-hydroxylation of lithocholic Acid, CYP3A levels and testosterone 6beta-hydroxylation (r2=0.7). Troleandomycin, a selective inhibitor of CYP3A enzymes, inhibited 6alpha-hydroxylation of Taurochenodeoxycholic Acid almost completely at a 10 microM concentration. Other inhibitors, such as alpha-naphthoflavone, sulfaphenazole and tranylcypromine had very little or no effect on the activity. The apparent Km for 6alpha-hydroxylation of Taurochenodeoxycholic by human liver microsomes was high (716 microM). This might give an explanation for the limited formation of 6alpha-hydroxylated bile Acids in healthy humans. From the present results, it can be concluded that CYP3A4 is active in the 6alpha-hydroxylation of both Taurochenodeoxycholic Acid and lithocholic Acid in human liver.
-
6α hydroxylation of Taurochenodeoxycholic Acid and lithocholic Acid by cyp3a4 in human liver microsomes
Biochimica et Biophysica Acta, 1999Co-Authors: Z Araya, K WikvallAbstract:The aim of the present study was to identify the enzymes in human liver catalyzing hydroxylations of bile Acids. Fourteen recombinant expressed cytochrome P450 (CYP) enzymes, human liver microsomes ...
-
6alpha-hydroxylation of Taurochenodeoxycholic Acid and lithocholic Acid byCYP3A4 in human liver microsomes.
1999Co-Authors: Z Araya, K WikvallAbstract:6alpha-hydroxylation of Taurochenodeoxycholic Acid and lithocholic Acid byCYP3A4 in human liver microsomes.
Kerstin Lundell - One of the best experts on this subject based on the ideXlab platform.
-
The porcine Taurochenodeoxycholic Acid 6alpha-hydroxylase (CYP4A21) gene: evolution by gene duplication and gene conversion.
Biochemical Journal, 2004Co-Authors: Kerstin LundellAbstract:Porcine Taurochenodeoxycholic Acid 6alpha-hydroxylase, cytochrome P450 4A21 (CYP4A21), differs from other members of the CYP4A subfamily in terms of structural features and catalytic activity. CYP4A21 participates in the formation of hyocholic Acid, a species-specific primary bile Acid in the pig. The CYP4A21 gene was investigated and found to be approx. 13 kb in size and split into 12 exons. The intron-exon organization of the CYP4A21 gene corresponds to that of CYP4A fatty Acid hydroxylase genes in other species. Comparison with a genomic segment of a pig CYP4A fatty Acid hydroxylase gene ( CYP4A24 ) revealed a sequence identity with CYP4A21 that extends beyond the exons, indicating a common origin by gene duplication. A pronounced sequence identity was found also within the proximal 5'-flanking regions, whereas the patterns of mRNA expression of CYP4A21 and CYP4A fatty Acid hydroxylases in pig liver differ. Sequence comparison aiming to elucidate the origin of the unique features of CYP4A21 revealed a region of decreased sequence identity from exon 6 to exon 8, strongly suggesting that gene conversion could have contributed to the evolution of CYP4A21.
-
Gene structure of pig sterol 12α-hydroxylase (CYP8B1) and expression in fetal liver: comparison with expression of Taurochenodeoxycholic Acid 6α-hydroxylase (CYP4A21)
Biochimica et biophysica acta, 2003Co-Authors: Kerstin Lundell, K WikvallAbstract:Cholic Acid is the major trihydroxy bile Acid formed in most mammals. The domestic pig (Sus scrofa) is an exception. The bile of adult pig is devoid of cholic Acid whereas hyocholic Acid is found in amounts equal to that of cholic Acid in humans. The pathway leading to formation of hyocholic Acid is believed to be species-specific and to have evolved in the pig to compensate for a nonexistent or deficient cholic Acid biosynthesis. However, a high level of cholic Acid has recently been found in the bile of fetal pig. Here we describe that a gene encoding the key enzyme in cholic Acid biosynthesis, the sterol 12alpha-hydroxylase (CYP8B1), is in fact present in the pig genome. The deduced amino Acid sequence shows 81% identity to the human and rabbit orthologues. CYP8B1 mRNA is expressed at significant levels in fetal pig liver. Both CYP8B1 and the key enzyme in hyocholic Acid formation, Taurochenodeoxycholic Acid 6alpha-hydroxylase (CYP4A21), were found to be expressed in pig liver in a developmental-dependent but opposite fashion.
-
Porcine Taurochenodeoxycholic Acid 6α-hydroxylase (CYP4A21) : gene organisation and aspects on the evolution of the CYP4A subfamily
2003Co-Authors: Kerstin LundellAbstract:Porcine Taurochenodeoxycholic Acid 6α-hydroxylase (CYP4A21) : gene organisation and aspects on the evolution of the CYP4A subfamily
-
Cloning and Expression of a Pig Liver Taurochenodeoxycholic Acid 6α-Hydroxylase (CYP4A21) A NOVEL MEMBER OF THE CYP4A SUBFAMILY
The Journal of biological chemistry, 2000Co-Authors: Kerstin Lundell, Ronnie Hansson, K WikvallAbstract:Abstract A cytochrome P450 expressed in pig liver was cloned by polymerase chain reaction using oligonucleotide primers based on amino Acid sequences of the purified Taurochenodeoxycholic Acid 6α-hydroxylase. This enzyme catalyzes a 6α-hydroxylation of chenodeoxycholic Acid, and the product hyocholic Acid is considered to be a primary bile Acid specific for the pig. The cDNA encodes a protein of 504 amino Acids. The primary structure of the porcine Taurochenodeoxycholic Acid 6α-hydroxylase, designated CYP4A21, shows about 75% identity with known members of the CYP4A subfamily in rabbit and man. Transfection of the cDNA for CYP4A21 into COS cells resulted in the synthesis of an enzyme that was recognized by antibodies raised against the purified pig liver enzyme and catalyzed 6α-hydroxylation of Taurochenodeoxycholic Acid. The hitherto known CYP4A enzymes catalyze hydroxylation of fatty Acids and prostaglandins and have frequently been referred to as fatty Acid hydroxylases. A change in substrate specificity from fatty Acids or prostaglandins to a steroid nucleus among CYP4A enzymes is notable. The results of mutagenesis experiments indicate that three amino Acid substitutions in a region around position 315 which is highly conserved in all previously known CYP4A and CYP4B enzymes could be involved in the altered catalytic activity of CYP4A21.
David Hercules - One of the best experts on this subject based on the ideXlab platform.
-
Quantification of bile Acids directly from plasma by MALDI-TOF-MS
Analytical and Bioanalytical Chemistry, 2004Co-Authors: Debralynn Mims, David HerculesAbstract:Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry (MS) has proved to be a useful method for the quantification of bile Acids directly from plasma. Six cholic Acid derivatives were selected for analysis: taurocholic Acid, Taurochenodeoxycholic Acid, taurolithocholic Acid, glycocholic Acid, glycochenodeoxycholic Acid, and glycolithocholic Acid. Solid-phase extraction (SPE) columns were used to preconcentrate and purify the plasma samples. Calibration curves averaged from 3 days were obtained for the bile Acids, and then tested for their ability to accurately determine concentrations from one measurement. In summary, a simple, rapid method has been developed for the quantification of bile salts from plasma by MALDI-MS with SPE cleanup.
-
Quantification of bile Acids directly from urine by MALDI-TOF-MS.
Analytical and bioanalytical chemistry, 2004Co-Authors: Debralynn Mims, David HerculesAbstract:Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry (MS) has proved to be a useful method for the quantification of bile Acids directly from plasma. Six cholic Acid derivatives were selected for analysis: taurocholic Acid, Taurochenodeoxycholic Acid, taurolithocholic Acid, glycocholic Acid, glycochenodeoxycholic Acid, and glycolithocholic Acid. Solid-phase extraction (SPE) columns were used to preconcentrate and purify the plasma samples. Calibration curves averaged from 3 days were obtained for the bile Acids, and then tested for their ability to accurately determine concentrations from one measurement. In summary, a simple, rapid method has been developed for the quantification of bile salts from plasma by MALDI-MS with SPE cleanup.
-
Quantification of bile Acids directly from urine by MALDI–TOF–MS
Analytical and Bioanalytical Chemistry, 2003Co-Authors: Debralynn Mims, David HerculesAbstract:The ability to quantify mixtures of bile Acids using matrix-assisted laser desorption/ionization time-of-flight (MALDI–TOF) mass spectrometry directly from urine has been demonstrated. Six cholic Acid derivatives were selected for analysis: taurocholic Acid (TCA), Taurochenodeoxycholic Acid (TCDCA), taurolithocholic Acid (TLCA), glycocholic Acid (GCA), glycochenodeoxycholic Acid (GCDCA), and glycolithocholic Acid (GCDCA). Urine samples were pre-concentrated and purified using solid-phase extraction (SPE) columns. The method was optimized to eliminate suppression effects, and proved to be reproducible from day to day. Calibration curves averaged from three days were obtained for the bile Acids directly from urine, and then tested for their ability to accurately determine concentrations from one measurement. In summary, a simple, rapid method has been developed for the quantification of bile salts from urine with SPE clean-up by MALDI-MS.
-
Quantification of bile Acids directly from urine by MALDI-TOF-MS.
Analytical and bioanalytical chemistry, 2003Co-Authors: Debralynn Mims, David HerculesAbstract:The ability to quantify mixtures of bile Acids using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry directly from urine has been demonstrated. Six cholic Acid derivatives were selected for analysis: taurocholic Acid (TCA), Taurochenodeoxycholic Acid (TCDCA), taurolithocholic Acid (TLCA), glycocholic Acid (GCA), glycochenodeoxycholic Acid (GCDCA), and glycolithocholic Acid (GCDCA). Urine samples were pre-concentrated and purified using solid-phase extraction (SPE) columns. The method was optimized to eliminate suppression effects, and proved to be reproducible from day to day. Calibration curves averaged from three days were obtained for the bile Acids directly from urine, and then tested for their ability to accurately determine concentrations from one measurement. In summary, a simple, rapid method has been developed for the quantification of bile salts from urine with SPE clean-up by MALDI-MS.
Aldo Roda - One of the best experts on this subject based on the ideXlab platform.
-
Mechanism for the prevention of cholestasis involving cytochrome P4503A overexpression.
Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 2000Co-Authors: Moreno Paolini, Francesco Piazza, Ester Speroni, Maria Clelia Guerra, Laura Pozzetti, Giorgio Cantelli-forti, Aldo RodaAbstract:BACKGROUND To clarify the preventive effect of taurohyodeoxycholic Acid on liver cholestasis induced by toxic bile Acids in rats, we evaluated whether modulation of cytochrome P4503A-linked oxidases is involved in the hepatic bile Acid retention and secretion mechanism. We investigated whether the safe or the toxic Taurochenodeoxycholic Acid, administered singly or together, affects cytochrome P450-catalyzed drug metabolism or biliary parameters. We also considered whether the inhibition of the P-glycoprotein export pump by vinblastine might be related to cytochrome P4503A overexpression. METHODS Hydroxylation of testosterone and N-demethylation of aminopyrine were studied in subcellular rat liver preparations after intravenous infusion of hepatoprotective and toxic bile Acids administered singly or together. Bile flow, calcium secretion, biliary enzymes activity, and secretion rates of the endogenous and administrated bile Acids were determined. CYP3A-dependent monooxygenases were also measured in the same coinfusion model in the presence of vinblastine. RESULTS Although wide modulation of the activities of different P450 subfamily of isoenzymes was seen, P4503A-associated monooxygenases showed similar patterns in the various situations, i.e., induction by taurohyodeoxycholic Acid, reduction by Taurochenodeoxycholic Acid, and protection (intermediate induction) in the coinfusion experiments. This correlates well with biliary parameters demonstrating the hepatoprotective ability of taurohyodeoxycholic Acid. Coadministration of bile Acids and vinblastine significantly modifies CYP3A-linked activities. CONCLUSIONS Bile Acid structure seems to be linked with hepatotoxicity/hepatoprotection and P4503A modulation. Taurohyodeoxycholic Acid could be therapeutic in cholestatic liver disease by inducing P4503A; we can hypothesize that an associated P-glycoprotein expression might facilitate biliary excretion of toxic Taurochenodeoxycholic Acid accumulated in the liver during cholestasis.
-
Competition in liver transport between chenodeoxycholic Acid and ursodeoxycholic Acid as a mechanism for ursodeoxycholic Acid and its amidates' protection of liver damage induced by chenodeoxycholic Acid
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 2000Co-Authors: Francesco Piazza, Marco Montagnani, Carmela Russo, Francesco Azzaroli, Rita Aldini, E. Roda, Aldo RodaAbstract:Abstract Background. Ursodeoxycholic Acid has been widely used as a therapeutic agent in cholesterol gallstones and liver disease patients, but its mechanism of action is still under investigation. Aims. The protective effect of ursodeoxycholic Acid, both free, taurine and glycine conjugated, against hepatotoxic bile Acids such as chenodeoxycholic Acid and its taurine amidate was studied in bile fistula rats and compared with the cholic and taurocholic Acid effect. Methods. Tauroursodeoxycholic Acid, glycine ursodeoxycholic Acid, ursodeoxycholic Acid, taurocholic Acid and cholic Acid were infused iv over 1 hour (8 μmol/min/kg) together with an equimolar dose of either Taurochenodeoxycholic Acid or chenodeoxycholc Acid. Bile flow, total and individual bile Acid and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. Results. Taurochenodeoxycholic Acid and chenodeoxycholc Acid caused cholestasis and liver damage associated with a decreased bile flow, total and individual bile Acids secretion accompanied by a biliary leakage of lactate dehydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic Acid, glycine ursodeoxycholic Acid, ursodeoxycholic Acid and taurocholic Acid, on the contrary, were choleretic, inducing an opposite effect on biliary parameters. Simultaneous infusion of Taurochenodeoxycholic Acid and the protective bile Acid resulted in a functional and morphological improvement of the above parameters in the following order: glycine ursodeoxycholic Acid > tauroursodeoxycholic Acid > ursodeoxycholic Acid followed by taurocholic Acid; cholic Acid was ineffective. Conclusions. The results show the protective effect of glycine ursodeoxycholic Acid, ursodeoxycholic Acid and tauroursodeoxycholic Acid. This may be due to a facilitated transport of the toxic bile Acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protective effect of ursodeoxycholic Acid and its amidates with respect to cholic Acid and its taurine conjugated form seems to be related to their different lipophilicity and micellar forming capacity.
-
taurohyodeoxycholic Acid protects against Taurochenodeoxycholic Acid induced cholestasis in the rat
Hepatology, 1998Co-Authors: Aldo Roda, Francesco Piazza, Mario Baraldini, Ester Speroni, Maria Clelia Guerra, C. Cerre, Giorgio Cantelli FortiAbstract:The prevention of the hepatotoxic effects produced by intravenous infusion of Taurochenodeoxycholic Acid (TCDCA) by coinfusion with taurohyodeoxycholic Acid (THDCA) was evaluated in bile fistula rats; the hepatoprotective effects of the latter were also compared with those of tauroursodeoxycholic Acid (TUDCA). Rats infused with TCDCA at a dose of 8 micromol/min/kg showed reduced bile flow and calcium secretion, as well as increased biliary release of alkaline phosphatase (AP) and lactate dehydrogenase (LDH). This was associated with a very low biliary secretion rate of TCDCA (approximately 1 micromol/min/kg). Simultaneous infusion of THDCA or TUDCA at the same dose preserved bile flow and almost totally abolished the pathological leakage of the two enzymes into bile. The effect was slightly more potent for THDCA. The maximum secretion rate of TCDCA increased to the highest value (8 micromol/min/kg) when coinfused with either of the two hepatoprotective bile Acids (BA), which were efficiently and completely secreted in the bile, without metabolism. Calcium output was also restored and phospholipid (PL) secretion increased with respect to the control saline infusion. This increase was higher in the THDCA study. These data show that THDCA is highly effective in the prevention of hepatotoxicity induced by intravenous infusion of TCDCA by facilitating its biliary secretion and reducing its hepatic residence time; this was associated with selective stimulation of PL biliary secretion.
-
Taurohyodeoxycholic Acid protects against Taurochenodeoxycholic Acid–induced cholestasis in the rat
Hepatology (Baltimore Md.), 1998Co-Authors: Aldo Roda, Francesco Piazza, Mario Baraldini, Ester Speroni, Maria Clelia Guerra, C. Cerre, Giorgio Cantelli FortiAbstract:The prevention of the hepatotoxic effects produced by intravenous infusion of Taurochenodeoxycholic Acid (TCDCA) by coinfusion with taurohyodeoxycholic Acid (THDCA) was evaluated in bile fistula rats; the hepatoprotective effects of the latter were also compared with those of tauroursodeoxycholic Acid (TUDCA). Rats infused with TCDCA at a dose of 8 micromol/min/kg showed reduced bile flow and calcium secretion, as well as increased biliary release of alkaline phosphatase (AP) and lactate dehydrogenase (LDH). This was associated with a very low biliary secretion rate of TCDCA (approximately 1 micromol/min/kg). Simultaneous infusion of THDCA or TUDCA at the same dose preserved bile flow and almost totally abolished the pathological leakage of the two enzymes into bile. The effect was slightly more potent for THDCA. The maximum secretion rate of TCDCA increased to the highest value (8 micromol/min/kg) when coinfused with either of the two hepatoprotective bile Acids (BA), which were efficiently and completely secreted in the bile, without metabolism. Calcium output was also restored and phospholipid (PL) secretion increased with respect to the control saline infusion. This increase was higher in the THDCA study. These data show that THDCA is highly effective in the prevention of hepatotoxicity induced by intravenous infusion of TCDCA by facilitating its biliary secretion and reducing its hepatic residence time; this was associated with selective stimulation of PL biliary secretion.
-
Metabolism, Pharmacokinetics, and Activity of a New 6-Fluoro Analogue of Ursodeoxycholic Acid in Rats and Hamsters
Gastroenterology, 1995Co-Authors: Aldo Roda, C. Cerre, Giorgio Cantelli Forti, Roberto Pellicciari, C. Polimeni, Bahman M. Sadeghpour, Ester Sapigni, Anna Maria Gioacchini, Benedetto NataliniAbstract:Abstract Background/Aims: The effectiveness of ursodeoxycholic Acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic Acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic Acid but with similar detergency. Methods: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of Taurochenodeoxycholic Acid was evaluated in bile fistula rats after intraduodenal coinfusion. Results: 6-Fluoro-ursodeoxycholic Acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic Acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile Acids (15% ursodeoxycholic Acid). The 6-fluoro analogue prevented the hepatotoxic effects of Taurochenodeoxycholic Acid. Conclusions: The results suggest that 6-fluoro-ursodeoxycholic Acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.
Giorgio Cantelli Forti - One of the best experts on this subject based on the ideXlab platform.
-
taurohyodeoxycholic Acid protects against Taurochenodeoxycholic Acid induced cholestasis in the rat
Hepatology, 1998Co-Authors: Aldo Roda, Francesco Piazza, Mario Baraldini, Ester Speroni, Maria Clelia Guerra, C. Cerre, Giorgio Cantelli FortiAbstract:The prevention of the hepatotoxic effects produced by intravenous infusion of Taurochenodeoxycholic Acid (TCDCA) by coinfusion with taurohyodeoxycholic Acid (THDCA) was evaluated in bile fistula rats; the hepatoprotective effects of the latter were also compared with those of tauroursodeoxycholic Acid (TUDCA). Rats infused with TCDCA at a dose of 8 micromol/min/kg showed reduced bile flow and calcium secretion, as well as increased biliary release of alkaline phosphatase (AP) and lactate dehydrogenase (LDH). This was associated with a very low biliary secretion rate of TCDCA (approximately 1 micromol/min/kg). Simultaneous infusion of THDCA or TUDCA at the same dose preserved bile flow and almost totally abolished the pathological leakage of the two enzymes into bile. The effect was slightly more potent for THDCA. The maximum secretion rate of TCDCA increased to the highest value (8 micromol/min/kg) when coinfused with either of the two hepatoprotective bile Acids (BA), which were efficiently and completely secreted in the bile, without metabolism. Calcium output was also restored and phospholipid (PL) secretion increased with respect to the control saline infusion. This increase was higher in the THDCA study. These data show that THDCA is highly effective in the prevention of hepatotoxicity induced by intravenous infusion of TCDCA by facilitating its biliary secretion and reducing its hepatic residence time; this was associated with selective stimulation of PL biliary secretion.
-
Taurohyodeoxycholic Acid protects against Taurochenodeoxycholic Acid–induced cholestasis in the rat
Hepatology (Baltimore Md.), 1998Co-Authors: Aldo Roda, Francesco Piazza, Mario Baraldini, Ester Speroni, Maria Clelia Guerra, C. Cerre, Giorgio Cantelli FortiAbstract:The prevention of the hepatotoxic effects produced by intravenous infusion of Taurochenodeoxycholic Acid (TCDCA) by coinfusion with taurohyodeoxycholic Acid (THDCA) was evaluated in bile fistula rats; the hepatoprotective effects of the latter were also compared with those of tauroursodeoxycholic Acid (TUDCA). Rats infused with TCDCA at a dose of 8 micromol/min/kg showed reduced bile flow and calcium secretion, as well as increased biliary release of alkaline phosphatase (AP) and lactate dehydrogenase (LDH). This was associated with a very low biliary secretion rate of TCDCA (approximately 1 micromol/min/kg). Simultaneous infusion of THDCA or TUDCA at the same dose preserved bile flow and almost totally abolished the pathological leakage of the two enzymes into bile. The effect was slightly more potent for THDCA. The maximum secretion rate of TCDCA increased to the highest value (8 micromol/min/kg) when coinfused with either of the two hepatoprotective bile Acids (BA), which were efficiently and completely secreted in the bile, without metabolism. Calcium output was also restored and phospholipid (PL) secretion increased with respect to the control saline infusion. This increase was higher in the THDCA study. These data show that THDCA is highly effective in the prevention of hepatotoxicity induced by intravenous infusion of TCDCA by facilitating its biliary secretion and reducing its hepatic residence time; this was associated with selective stimulation of PL biliary secretion.
-
Metabolism, Pharmacokinetics, and Activity of a New 6-Fluoro Analogue of Ursodeoxycholic Acid in Rats and Hamsters
Gastroenterology, 1995Co-Authors: Aldo Roda, C. Cerre, Giorgio Cantelli Forti, Roberto Pellicciari, C. Polimeni, Bahman M. Sadeghpour, Ester Sapigni, Anna Maria Gioacchini, Benedetto NataliniAbstract:Abstract Background/Aims: The effectiveness of ursodeoxycholic Acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic Acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic Acid but with similar detergency. Methods: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of Taurochenodeoxycholic Acid was evaluated in bile fistula rats after intraduodenal coinfusion. Results: 6-Fluoro-ursodeoxycholic Acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic Acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile Acids (15% ursodeoxycholic Acid). The 6-fluoro analogue prevented the hepatotoxic effects of Taurochenodeoxycholic Acid. Conclusions: The results suggest that 6-fluoro-ursodeoxycholic Acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.
