Physicochemical and physiological properties of 5α-cyprinol sulfate, the toxic bile salt of cyprinid fish

Abstract

5α-Cyprinol sulfate was isolated from bile of the Asiatic carp, Cyprinus carpio. 5α-Cyprinol sulfate was surface active and formed micelles; its critical micellization concentration (CMC) in 0.15 M Na+ using the maximum bubble pressure device was 1.5 mM; by dye solubilization, its CMC was ∼4 mM. At concentrations >1 mM, 5α-cyprinol sulfate solubilized monooleylglycerol efficiently (2.1 molecules per mol micellar bile salt). When infused intravenously into the anesthetized rat, 5α-cyprinol sulfate was hemolytic, cholestatic, and toxic. In the isolated rat liver, it underwent little biotransformation and was poorly transported (Tmax ≅ 0.5 μmol/min/kg) as compared with taurocholate. 5α-Cyprinol, its bile alcohol moiety, was oxidized to its corresponding C27 bile acid and to allocholic acid (the latter was then conjugated with taurine); these metabolites were efficiently transported. 5α-Cyprinol sulfate inhibited taurocholate uptake in COS-7 cells transfected with rat asbt, the apical bile salt transporter of the ileal enterocyte. 5α-Cyprinol had limited aqueous solubility (0.3 mM) and was poorly absorbed from the perfused rat jejunum or ileum. Sampling of carp intestinal content indicated that 5α-cyprinol sulfate was present at micellar concentrations, and that it did not undergo hydrolysis during intestinal transit.These studies indicate that 5α-cyprinol sulfate is an excellent digestive detergent and suggest that a micellar phase is present during digestion in cyprinid fish. 5α-Cyprinol sulfate was isolated from bile of the Asiatic carp, Cyprinus carpio. 5α-Cyprinol sulfate was surface active and formed micelles; its critical micellization concentration (CMC) in 0.15 M Na+ using the maximum bubble pressure device was 1.5 mM; by dye solubilization, its CMC was ∼4 mM. At concentrations >1 mM, 5α-cyprinol sulfate solubilized monooleylglycerol efficiently (2.1 molecules per mol micellar bile salt). When infused intravenously into the anesthetized rat, 5α-cyprinol sulfate was hemolytic, cholestatic, and toxic. In the isolated rat liver, it underwent little biotransformation and was poorly transported (Tmax ≅ 0.5 μmol/min/kg) as compared with taurocholate. 5α-Cyprinol, its bile alcohol moiety, was oxidized to its corresponding C27 bile acid and to allocholic acid (the latter was then conjugated with taurine); these metabolites were efficiently transported. 5α-Cyprinol sulfate inhibited taurocholate uptake in COS-7 cells transfected with rat asbt, the apical bile salt transporter of the ileal enterocyte. 5α-Cyprinol had limited aqueous solubility (0.3 mM) and was poorly absorbed from the perfused rat jejunum or ileum. Sampling of carp intestinal content indicated that 5α-cyprinol sulfate was present at micellar concentrations, and that it did not undergo hydrolysis during intestinal transit. These studies indicate that 5α-cyprinol sulfate is an excellent digestive detergent and suggest that a micellar phase is present during digestion in cyprinid fish. In vertebrates, cholesterol is eliminated by conversion to water-soluble amphipathic, functional molecules called bile salts. Bile salts can be divided into three classes based on side-chain structure: C27 bile alcohols, C27 bile acids, and C24 bile acids (1Hofmann A.F. Schteingart C.D. Hagey L.R. Species differences in bile acid metabolism.in: Paumgartner G. Beuers U. Bile Acids in Liver Diseases. Kluwer Academic Publishers, Boston, MA1995: 3-30Google Scholar). After their biosynthesis from cholesterol, bile alcohols and bile acids undergo “conjugation,” a biotransformation step that renders them water soluble and membrane impermeable at physiological pH. Bile alcohols are conjugated by esterification of the terminal C-27 hydroxy group with sulfate, whereas bile acids are usually conjugated by N-acyl amidation of the terminal C-27 or C-24 carboxyl group with taurine or glycine (2Hofmann A.F. Bile acids.in: Arias I.M. Boyer J.L. Fausto N. Jakoby W.B. Schachter D.A. Shafritz D.A. The Liver: Biology and Pathobiology. Third Edition. Raven Press, New York1994: 677-718Google Scholar, 3Une M. Hoshita T. Natural occurrence and chemical synthesis of bile alcohols, higher bile acids, and short side chain bile acids.Hiroshima J. Med. Sci. 1994; 43: 37-67PubMed Google Scholar). The occurrence of C27 bile alcohol sulfates is widespread in nature. They are the dominant bile salts of ancient mammalian species (elephant, manatee, hyrax, and rhinoceros) (4Hagey L.R. Bile Acid Biodiversity in Vertebrates: Chemistry and Evolutionary Implication. University of California–San Diego, San Diego, CA1992Google Scholar). They are also the major biliary surfactants present in cartilaginous fish (sharks, rays, and skates), herbivorous bony fish (carp, arapima, and angelfish), and in some amphibians (salamanders and frogs) (3Une M. Hoshita T. Natural occurrence and chemical synthesis of bile alcohols, higher bile acids, and short side chain bile acids.Hiroshima J. Med. Sci. 1994; 43: 37-67PubMed Google Scholar, 5Haslewood G.A.D. The Biological Importance of Bile Salts. North-Holland Publishing Co., Amsterdam, The Netherlands1978Google Scholar). One of the common bile alcohols is 5α-cyprinol, a molecule with five hydroxy groups that was originally isolated from the bile of Cyprinus carpio, the Asiatic carp. Cyprinol was shown to have hydroxy groups at C-3, C-7, C-12, C-26, and C-27, based on the work of Hoshita, Magayoshi, and Kazuno (6Hoshita T. Nagayoshi S. Kazuno T. Stero-bile acids and bile alcohols LIV. Studies on the bile of carp.J. Biochem. 1963; 54: 369-373Crossref PubMed Scopus (19) Google Scholar) and Anderson, Briggs, and Haslewood (7Anderson I.G. Briggs T. Haslewood G.A.D. Comparative study of bile salts. 18. The chemistry of cyprinol.Biochem. J. 1964; 90: 303-308Crossref PubMed Scopus (11) Google Scholar). Confirmation of the structure of the sulfate ester of 5α-cyprinol by proton and 13C-NMR as well as mass spectrometry (MS) has been reported by Asakawa et al. (8Asakawa M. Noguchi T. Seto H. Furihata K. Fujikura K. Hashimoto K. Structure of the toxin isolated from carp (Cyprinus carpio) bile.Toxicon. 1990; 28: 1063-1069Crossref PubMed Scopus (19) Google Scholar) 7Chemical Abstracts has assigned the registry number 15066-41-8 to 5α-cyprinol sulfate. Its index name is Cholestane-3,7,12,26,27-pentol, hydrogen sulfate, (3α,5α,7α,12α)−. The assignment of the sulfate to C-27 versus C-26 is arbitrary.. The A/B ring juncture of cyprinol is 5α (A/B trans), whereas the structure of most C27 and C24 bile acids is 5β (A/B cis). It has become customary to add a 5α prefix to cyprinol to indicate clearly its 5α-A/B trans juncture, and thus distinguish it from 5β-cyprinol (A/B cis), which is present in other fish, such as the sturgeon (9Haslewood G.A.D. Tammar A.R. Comparative studies of bile salts. Bile salts of sturgeons (Acipenseridae) and of the paddlefish Polyodon spathula: a new partial synthesis of 5 beta cyprinol.Biochem. J. 1968; 108: 263-268Crossref PubMed Scopus (10) Google Scholar). The structure of 5α-cyprinol sulfate is shown in Fig. 1. Most natural bile acids are amphipathic, possessing a hydrophilic side and a hydrophobic side (10Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar). The amphipathic structure of bile acids is responsible for their chief physiological function, which is to enhance absorption of dietary lipids. The C24 bile acids readily form mixed micelles with fatty acids and monoglycerides, and such mixed micelles can in turn solubilize fat-soluble vitamins. Such solubilization greatly enhances diffusion of insoluble lipids to the enterocyte brush border (11Hofmann A.F. Mysels K.J. Bile salts as biological surfactants.Colloids Surf. 1988; 30: 145-173Crossref Scopus (165) Google Scholar). The physicochemical properties of C24 bile acids have been investigated extensively (12Carey M.C. Physical-chemical properties of bile acids and their H. J. and Bile Scopus Google Scholar, chemistry of of The studies have the physicochemical properties of C27 bile acids and C27 bile that the and solubilization properties of 5α-cyprinol sulfate be to of a molecule with a as shown in Fig. and studies to also limited physiological studies on its ileal and in of its for The and in the rat of a from the bile of the carp PubMed Scopus Google Scholar, T. K. K. K. T. Cyprinol as water-soluble of carp.J. Scopus (11) Google Scholar, of carp bile and sulfate in Biochem. PubMed Scopus Google Scholar, fish a from J. Full Text Full Text PDF PubMed Scopus Google in fish a from J. Full Text Full Text PDF PubMed Scopus Google some properties of 5α-cyprinol, the bile alcohol of 5α-cyprinol sulfate, in to the in of hydrolysis of the ester sulfate to the bile of were from a fish and an and in 5α-Cyprinol sulfate was isolated from the of carp The was to using a 5 to with J. T. The was in of carp bile was at the of the of in was to the 5α-cyprinol sulfate. were by using a for conjugated bile acids A.F. of and conjugated bile acids on Full Text PDF Google Scholar). 5α-cyprinol sulfate were and to on a The structure of 5α-cyprinol sulfate was by proton was at in the of University of San The was and chemical are in to and and 5α-Cyprinol sulfate was from the of carp by the of of The was in and at for A. M. A.F. for the of and bile acids in PubMed Scopus Google the in of the 5α-cyprinol sulfate. and were The phase was to was by using with in the of were by A.F. of and conjugated bile acids on Full Text PDF Google and 5α-cyprinol were to of 5α-cyprinol that was by The of 5α-cyprinol was by The critical micellization is the at which the solubility of the the critical micellization concentration At is a phase and of 5α-cyprinol sulfate in water was at and for to 5α-cyprinol sulfate from were three bile salt concentrations mM, 5 mM, and the 5 and concentrations, was in concentrations 0.5 and the bile salt was at the and M. of the salts of three other conjugated C24 bile acids and were were at and in a with a to for The was as a with an of for Hofmann A.F. Mysels K.J. A. The of and concentration on the properties of aqueous of glycine conjugated bile Sci. Scopus Google Scholar). The the bile salt concentration at which was not present and the concentration at which it was present was to the of 5α-cyprinol was in water and for The was then for to the insoluble One of in was to the was to to using and by The concentration of 5α-cyprinol was from the The CMC of 5α-cyprinol sulfate was in The was based on the in surface in to aqueous concentration using the maximum bubble pressure device was The device was with water and a bubble of was of and 5α-cyprinol sulfate were in bile and the in bubble pressure as the were with M The CMC was as the of the by the of the surface was the of the bile salt concentration (10Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar). The CMC was also by a dye solubilization using a of micelles are and the solubilized is to the concentration of was the three the and to the The of of with the was as the were at the with taurocholate to of the CMC of a 5α-cyprinol sulfate with that of a bile acid the CMC by the maximum bubble pressure and the dye solubilization are to well (10Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar). bile acid are to with molecules such as monoglycerides, in micelles formed at concentrations well the CMC of a bile acid The CMC of 5α-cyprinol sulfate in the of monooleylglycerol as well as its for was by as A.F. The of bile salts in the properties of micellar of conjugated bile J. 1963; PubMed Scopus Google Scholar). to and biotransformation of 5α-cyprinol sulfate in the anesthetized biliary rat not be the of 5α-cyprinol sulfate at the physiological of that is physiological for of conjugated C24 bile acids in the and studies of and biotransformation were using the as in U. Schteingart C.D. Hofmann A.F. of bile acids and in uptake and Full Text PDF PubMed Scopus Google Scholar). In the is perfused with an with were infused for at a physiological natural conjugated bile acids in the of or at Bile was in 5 for was and bile salt was by the to bile acids of the for bile acids in Google Scholar). was by the bile salt concentration in the and of 5α-cyprinol sulfate and 5α-cyprinol was by a of These to bile acid biotransformation J. K.J. Hagey L.R. Hofmann A.F. of side chain in with a PubMed Scopus Google using a for of conjugated bile acids J.L. Hofmann A.F. pressure of conjugated bile acids in of and and the common conjugated bile 28: Full Text PDF PubMed Google L.R. Hofmann A.F. bile acid of the Sci. Scopus Google and bile acids were isolated by of was at to bile acids present in was also on from was at the of Biology and The The was a in the or The was and the to the were in a phase at a of The was at and the to was and using A. M. A.F. for the of and bile acids in PubMed Scopus Google Scholar) to of 5α-cyprinol sulfate with taurocholate by the an of 5α-cyprinol sulfate from was a of of was in 5 of the 5α-cyprinol sulfate on taurocholate uptake was by in the and 5α-cyprinol was absorbed from the it was perfused into the jejunum or the of the anesthetized biliary rat using a perfused at a that the Schteingart C.D. Hofmann A.F. J. A. absorption of conjugated bile acids in and of the ileal in the Full Text PDF PubMed Google Scholar). The 5α-cyprinol at concentration and acid at mM, the latter an that be in bile conjugated The and as well as a to The was to the ileal to The intestinal was perfused for and bile was for in bile during the of biliary was for as well as by to of for taurocholate uptake by 5α-cyprinol sulfate and 5α-cyprinol was in COS-7 cells transfected with asbt, the conjugated bile acid transporter present in the apical membrane of the ileal enterocyte M. S. of rat and ileal bile acid in J. Google Scholar). taurocholate uptake was by transfected COS-7 cells with in or 5α-Cyprinol sulfate or 5α-cyprinol was to the at concentrations from to After for at the cells were three with of and with 0.5 in were to and carp were at a fish were for of the for bile acids in Google Scholar) of the concentration of 5α-cyprinol sulfate. other carp were and The concentration of 5α-cyprinol sulfate in the was of the for bile acids in Google Scholar). from and were by A.F. of and conjugated bile acids on Full Text PDF Google Scholar) to 5α-cyprinol was carp bile 5α-cyprinol sulfate and of a the of a C27 bile alcohol sulfate with hydroxy is most Bile of 5 from carp Biochem. Google Scholar) with sulfate at C-26 Bile of 5 from carp Biochem. Google Scholar). Bile acids were not have been reported to be present in some of carp bile Bile of 5 from carp Biochem. Google Scholar). in the indicated that are not present in carp cholesterol was present in of 5α-cyprinol sulfate was at that its was The of was The salt of 5α-cyprinol sulfate was soluble that of and soluble that of salt has an of Hofmann A.F. Mysels K.J. A. The of and concentration on the properties of aqueous of glycine conjugated bile Sci. Scopus Google Scholar). The aqueous solubility of 5α-cyprinol was a to that of acid A. A. of hydroxy on aqueous solubility and of bile Scopus Google Scholar). 5α-cyprinol was poorly soluble and did not form the surface and bile salt concentration for the 5α-cyprinol sulfate and The surface for molecule with The CMC was mM; concentration is a concentration at which of Na+ is present at 0.15 M. the solubilization of by the 5α-cyprinol sulfate and taurocholate. The CMC of 5α-cyprinol sulfate by was mM; that of taurocholate was mM. were with a of M. the solubilization of monooleylglycerol by 5α-cyprinol sulfate and taurocholate. 5α-cyprinol sulfate, solubilization at mM, and for at mM. The of the solubilization bile was for 5α-cyprinol sulfate, a that for which was 5α-cyprinol sulfate was infused at a of for into the of bile The major had the of 5α-cyprinol sulfate. had a with its a of 5α-cyprinol by its it did not were to and the had the of 5α-cyprinol sulfate was transported biotransformation for a that underwent of 5α-cyprinol sulfate at the of was At the of was of 5α-cyprinol sulfate undergo hydrolysis during the of 5α-cyprinol was also in the Bile the of 5α-cyprinol 5α-cyprinol by not of bile the of a was with the taurine of allocholic acid and a Bile was and with in to bile acids or bile alcohols present in was with and the hydroxy groups to a of The bile acids and alcohols in the aqueous phase and were to a into with to and to in to the major bile acids of the rat and were The major was allocholic the was These indicate that in the infused at a of 5α-cyprinol is to allocholic acid and the C27 bile acid of 5α-cyprinol The allocholic acid was efficiently conjugated with In the C27 bile acid of 5α-cyprinol was with taurine to a limited and was into bile in of on by also metabolites of These an a sulfate and a these were such were not The of 5α-cyprinol in the is in Fig. When 5α-cyprinol sulfate was infused at a of uptake was during the not of cyprinol sulfate and its to a maximum at The of was 0.5 and in bile When infused at 5α-cyprinol sulfate was at 0.5 to be its in the at a for to that 5α-cyprinol sulfate had been into the and was to be into μmol/min/kg) of 5α-cyprinol sulfate bile to as as it was Bile the the of 5α-cyprinol sulfate When 5α-cyprinol, the bile alcohol of 5α-cyprinol sulfate, was infused at a of biliary of its metabolites a at of 5α-cyprinol in the chemical form of and the C27 acid was of the biotransformation was to the The of 5α-cyprinol a in bile with its higher C24 and C27 bile In using the the of an of 5α-cyprinol sulfate during taurocholate a in taurocholate uptake by the as well as in taurocholate in The on uptake was the of 5α-cyprinol sulfate was the was an in taurocholate of taurocholate the and not of the of 5α-cyprinol sulfate, its absorption not be by biliary during ileal in the anesthetized biliary rat, as is Schteingart C.D. Hofmann A.F. J. A. absorption of conjugated bile acids in and of the ileal in the Full Text PDF PubMed Google Scholar). of 5α-cyprinol sulfate and 5α-cyprinol with was using COS-7 cells transfected with 5α-Cyprinol sulfate at a concentration of inhibited the uptake of taurocholate at of taurocholate was also inhibited in a by 5α-cyprinol, with of at a concentration of 5α-cyprinol was into C24 and C27 bile acids that were efficiently in it was to the absorption of 5α-cyprinol from the perfused jejunum and ileum. was in the concentration of in the that during the In the the absorption of 5α-cyprinol was that of In the perfused the absorption of 5α-cyprinol was that of The absorption of 5α-cyprinol was in the in the whereas acid was absorbed as from the jejunum as from the ileum. When infused into the the biotransformation of 5α-cyprinol was to that in the anesthetized biliary 5α-cyprinol was biotransformation of 5α-cyprinol during the enterocyte is The concentration 5α-cyprinol sulfate in the carp was In the intestinal content the concentration of 5α-cyprinol sulfate was that mixed micelles are present during of intestinal the indicated that 5α-cyprinol was that of 5α-cyprinol sulfate not during intestinal transit. These indicate that 5α-cyprinol sulfate has excellent physicochemical properties as a digestive Its were at that it is an excellent Its salt had a aqueous of its salt in the biliary the concentration of is A.F. Mysels K.J. Bile acid solubility and in and in the of and Full Text PDF PubMed Google Scholar). an ester sulfate, its is and the be and soluble at the in the during digestion to the three groups as 5α-cyprinol sulfate had a CMC that was The CMC of 5α-cyprinol sulfate can be by its side chain (10Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar). The CMC of the C27 acid is to be its C24 properties of taurine and to in Med. Scholar). 5α-Cyprinol sulfate with monoglycerides, mixed micelles mM. It solubilized to a of the natural conjugated bile acids present in bile A.F. The of bile salts in the properties of micellar of conjugated bile J. 1963; PubMed Scopus Google Scholar). 5α-Cyprinol sulfate is present in micellar concentrations in the carp and other cyprinid fish, and is thus an for the absorption of dietary lipids. 5α-Cyprinol sulfate was not during a was to a In the 5α-cyprinol sulfate was poorly transported into bile as compared with taurocholate. Its of 0.5 was that of taurocholate μmol/min/kg) U. Schteingart C.D. Hofmann A.F. of bile acids and in uptake and Full Text PDF PubMed Scopus Google Scholar). 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