Study of CD4 and CD8 level and graft versus host reaction during xenotransplantation of UV-B irradiated hepatocytes . Dept. of Gastroenterology, Osmania General Hospital, Afzalgunj, Hyderabad, Pin 500 012, INDIA
Journal: Hepatology (1995)

A series of unconjugated and taurine conjugated bile acids (BAs) differing in water solubility (SWo), critical micellar concentration (CMC), and hydrophilicity (K′) were infused iv to rats at a tracer dose and a dose of 6 μmol/min/kg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids secretions, and bile flow. The BAs studied differ in the number (2–3), position (−3, −6, −7, −12), and orientation of the hydroxyls (α/β); the side chain structure was modified by shortening (C-23, nor-BA) and by lengthening (C-25, homo-BA), while maintaining the same structure of nuclear hydroxyls (3α7β). At a “tracer” dose, all C-24 natural BAs are efficiently recovered in bile when administered in both unconjugated and taurine conjugated forms. At a “high dose”, all taurine conjugated BAs are efficiently recovered in bile (80–100%). However, a variable recovery was observed among unconjugated BAs: trihydroxy BAs are efficiently recovered (85–100%), while dihydroxy BAs are only partially recovered (25–40%). The side chain-modified BAs [i.e., C-23 nor and C-25 homo analogs of ursodeoxycholic acid (UDCA)] are partially recovered at a tracer dose (20–30%), but less at a high dose (10–20%) when administered in the unconjugated form. In contrast, the corresponding taurine conjugates are more efficiently recovered in bile (60–80%). Conjugation with taurine increases total recovery of unconjugated BAs in bile by not more than 30–40%. Highly hydrophilic and water-soluble BAs, such as ursocholic acid (SWo = 1.67 mM) and cholic acid (SWo = 0.27 mM), can also be secreted as unconjugates, and this accounts for their complete recovery. The conjugation step is rate limiting for poorly soluble BAs such as ursodeoxycholic acid (SWo = 0.009 mM) when administered at a high dose, and critical for nor and homo analogs which are poorly soluble and whose side chain modification partially suppresses their conjugation with taurine or glycine and thereby induces alternative pathways such as glucuronidation or sulfation. The induced bile flow is directly related to the hydrophilicity of the natural C-24 bile acid. The C-23 analog of UDCA greatly increased bile flow, which reached a maximum at very low BA secretion, and the effect is drastically reduced when it was administered as taurine conjugates. The phospholipids and, to a lesser extent, the cholesterol secretions are poorly related to both the hydrophilicity and CMC of BAs, and hepatic biotransformations play a major role in modulating the biliary lipid secretion. In addition, specific effects not related to physicochemical properties, such as selective inhibition of cholesterol synthesis, were observed (see chenodeoxycholic acid and hyocholic acid). The quantitative parameters here evaluated by means of a factor analysis could be useful in structure–activity relationship studies and in designing BA analogs; the properties of homo-UDCA as a new synthetic BA are also discussed.