Faculty Bibliography

The metabolism and excretion of chenodeoxycholic acid-3-sulfate were determined in rats and hamsters. Constant intravenous infusions of 1, 2, and 3 mumoles/min in rats gave a maximum excretion in bile of 1.25 mumoles/min. Simultaneous infusions of sodium taurocholate at 2.0 mumoles/min and sulfobromophthalein at 0.2 mumole/min had no effects on the maximum excretion rate of chenodeoxycholic acid-3-sulfate. However, the bile acid ester sulfate caused a dose-related reduction in the excretion rate of BSP without affecting bile acid excretion rate and without a reduction in total bile flow. Chromatographic analysis of ester sulfate, a bile acid recovered in bile and urine, indicated that more than 95% had not undergone further metabolic transformation

The effect of 26-hydroxycholesterol and other intermediates in bile acid synthesis on HMG-CoA reductase activity was studied in Chinese hamster ovary (CHO) cell culture. Incubation of CHO cells for 5 hr in 0.25 microM 26-hydroxycholesterol caused a 40% inhibition of HMG-CoA reductase activity. All other intermediates tested including 3 beta-hydroxy-5-cholenoic acid and cholest-5-ene-3 beta,7 alpha,26-triol, oxidation products of 26-hydroxycholesterol, had little or no inhibitory effect. It is proposed that 26-hydroxycholesterol has a selective biological role in the regulation of cholesterol synthesis

The quantitative significance of the metabolism of 3 beta, 7 alpha-dihydroxy-5-cholen-24-oic acid to chenodeoxycholic acid was evaluated in the hamster. A precursor-product relationship was established in this species by the finding that intravenous administration to an animal previously given cholesterol-4-14C caused a significant reduction in the specific activity of chenodeoxycholic acid. Administration of 12.9 mumole of the precursor was followed by a 10-fold increase in chenodeoxycholic acid excretion although the predominant excretory pathway was via biliary excretion as a monosulfate. The data indicate that synthesis of bile acid from cholesterol via the intermediate 3 beta, 7 alpha-dihydroxy-5-cholen-24-oic acid can be a quantitatively important pathway

Biliary colic in the absence of demonstrable stones--and, indeed, in the absence of a gallbladder--has long been mystifying. Evidence is growing for the existence of purely functional disease of the biliary system. Although the mechanisms have not been fully elucidated, investigative procedures seem to provide a clinical basis for the diagnosis of biliary dyskinesia

Serum 26-hydroxycholesterol was quantitated by isotope dilution-mass spectrometry in normal individuals and in patients with cerebrotendinous xanthomatosis. In the normal individuals, the concentration of 26-hydroxycholesterol in serum ranged from 4.3 to 13.0 microgram/100 ml. In five patients with CTX, 26-hydroxycholesterol in serum ranged from 0 to 0.6 microgram/100 ml. The findings can be explained by reduced or absent mitochondrial C27 steroid 26-hydroxylase activity. The method is useful for detection of CTX and perhaps other disturbances of sterol and bite acid metabolism

The hepatotoxic effects of cholelitholytic bile acids, ursodeoxycholic and chenodeoxycholic acids, were compared with each other and with those of lithocholic acid, a known hepatotoxic bile acid, in the rabbit. Male New Zealand white rabbits were fed regular laboratory chow containing ursodeoxycholic, chenodeoxycholic, or lithocholic acid at a concentration of 0.5 per cent (w/w) for 14 days. The control group was fed the chow without added bile acids. The mortality rate was highest (six of 12) in the lithocholate group, intermediate (two of eight) in the chenodeoxycholate group, and lowest (none of six) in the ursodeoxycholate group. Light microscopy of the liver revealed fibrosis, inflammation, and bile duct proliferation in the portal regions in the three experimental groups; however, the lesions in the lithocholate and chenodeoxycholate groups were more severe and often associated with periportal extension of fibrosis and focal necrosis of the parenchyma. In addition, electron microscopy revealed distortion of bile canaliculi, conspicuous bundles of intermediate-sized filaments, expansion of pericanalicular cytoplasmic matrix due to apparent accumulation of microfilaments, prominence of lysosomes, and fragmentation of cisternae of the rough endoplasmic reticulum. These ultrastructural changes were less marked and often absent in the ursodeoxycholate group. The serum L-alanine aminotransferase activity increased 5- to 6-fold in the lithocholate and chenodeoxycholate groups, whereas it remained less than 2-fold of the control level in the ursodeoxycholate group on day 14. The serum lithocholate concentration was markedly elevated to comparable levels in all three groups, whereas ursodeoxycholate was highly increased in the ursodeoxycholate group but undetectable in the other groups at the time of sacrifice. It is concluded that (1) although the oral administration of three bile acids induces hepatic injuries in the rabbit, ursodeoxycholate causes less severe injury than do the other two, (2) the advantage of ursodeoxycholate versus chenodeoxycholate is probably relative rather than absolute, (3) lithocholate formed through metabolic conversion from ursodeoxycholate may be responsible for the most part for hepatotoxicity, and (4) it is possible that the concurrent presence of ursodeoxycholate may mitigate lithocholate's hepatotoxicity