3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.
3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale Università degli Studi di Perugia, 06122 Perugia, Italy. clerici@unipg.it
Carlo
C
Clerici
Danilo
D
Castellani
Stefania
S
Asciutti
Roberto
R
Pellicciari
Kenneth D R
KD
Setchell
Nancy C
NC
O'Connell
Bahman
B
Sadeghpour
Emidio
E
Camaioni
Stefano
S
Fiorucci
Barbara
B
Renga
Elisabetta
E
Nardi
Giuseppe
G
Sabatino
Mattia
M
Clementi
Vittorio
V
Giuliano
Monia
M
Baldoni
Stefano
S
Orlandi
Alessandro
A
Mazzocchi
Antonio
A
Morelli
Olivia
O
Morelli
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D002757:Cholanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008823:Micelles; D015394:Molecular Structure; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013259:Steroids, Fluorinated / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology
C513118:3,6-dihydroxy-7-fluorocholanoic acid; D002757:Cholanes; D008823:Micelles; D010743:Phospholipids; D012333:RNA, Messenger; D013259:Steroids, Fluorinated; D003840:Deoxycholic Acid; D004997:Ethinyl Estradiol; D014580:Ursodeoxycholic Acid; D002790:Cholesterol 7-alpha-Hydroxylase; D013253:Steroid 12-alpha-Hydroxylase