Clerici Carlo, Castellani Danilo, Asciutti Stefania, Pellicciari Roberto, Setchell Kenneth D R, O'Connell Nancy C, Sadeghpour Bahman, Camaioni Emidio, Fiorucci Stefano, Renga Barbara, Nardi Elisabetta, Sabatino Giuseppe, Clementi Mattia, Giuliano Vittorio, Baldoni Monia, Orlandi Stefano, Mazzocchi Alessandro, Morelli Antonio, Morelli Olivia
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale Università degli Studi di Perugia, 06122 Perugia, Italy.
Toxicol Appl Pharmacol. 2006 Jul 15;214(2):199-208. doi: 10.1016/j.taap.2005.12.017. Epub 2006 Feb 17.
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.
3α-6α-二羟基-7α-氟-5β-胆烷酸酯（UPF-680）是猪去氧胆酸（HDCA）的7α-氟类似物，其合成目的是提高熊去氧胆酸（UDCA）的生物利用度和稳定性。采用急性大鼠胆瘘模型和由17α-乙炔基雌二醇（17EE）诱导的慢性胆汁淤积模型，研究并比较了UPF-680（剂量范围为0.6 - 6.0微摩尔/千克·分钟）和UDCA对胆汁流量、胆汁碳酸氢盐（HCO₃⁻）、脂质输出、胆汁酸组成、肝酶和有机阴离子转运体的影响。在急性输注中，UPF-680以剂量相关方式增加胆汁流量，最高可达40.9%。胆汁HCO₃⁻输出也有类似增加。仅在最高剂量时观察到磷脂分泌有变化。用UDCA和UPF-680治疗可逆转17EE诱导的慢性胆汁淤积；在该模型中，与显著增加胆汁流量的UPF-680相比，UDCA对胆汁流量无影响。急性给予UPF-680时，胆汁酸池富含未结合和结合的UPF-680（71.7%），内源性胆酸和鼠胆酸异构体减少。长期给予UPF-680或UDCA时，主要胆汁酸为牛磺酸共轭物，但UPF-680对胆汁酸池的改变更大。UPF-680增加细胞色素P450 7A1（CYP7A1）和细胞色素P450 8B（CYP8B）的mRNA表达。UDCA和UPF-680均增加牛磺胆酸盐共转运多肽（NCTP）的mRNA表达。总之，UPF-680可预防17EE诱导的胆汁淤积，并用较少的去污剂和细胞毒性胆汁酸丰富胆汁酸池。这种新型氟化胆汁酸可能在胆汁淤积性肝病治疗中具有潜力。
