Robert H. Palmer

PYROGENIC AND INFLAMMATORY PROPERTIES OF CERTAIN BILE ACIDS IN MAN

This is a report on the pyrogenic and inflammatory properties of certain bile acids in man. The study was prompted by the structural similarity between these acidic steroids and the pyrogenic neutral steroids described previously (2-7). In addition, it seemed important to establish whether the large quantities of steroid acids formed during the metabolism of cholesterol could serve as a source of endogenous compounds having fever-producing action in man.

Lack of effect of lovastatin therapy on the parameters of whole-body cholesterol metabolism.

UNLABELLED The effects of lovastatin therapy on the parameters of body cholesterol metabolism were explored in nine hypercholesterolemic patients. Long-term cholesterol turnover studies were performed before therapy, and were repeated after 15 mo of lovastatin therapy (40 mg/d) while continuing on therapy. The major question addressed was whether a reduction in plasma cholesterol level with lovastatin would be associated with a reduction in the whole-body production rate of cholesterol or with the sizes of exchangeable body cholesterol pools as determined by the three-pool model of cholesterol turnover. The mean plasma cholesterol level decreased 19.4% (from 294 to 237 mg/dl), and low-density lipoprotein cholesterol decreased 23.8% (from 210 to 159 mg/dl) with lovastatin therapy. Changes in high-density lipoprotein cholesterol level were not significant. The cholesterol production rate did not change significantly with therapy (1.09 +/- 0.10 [mean +/- S.D.] vs. 1.17 +/- 0.09 g/d). By comparison, colestipol and niacin treatment in three other subjects more than doubled the cholesterol production rate (1.14 +/- 0.28 vs. 2.42 +/- 0.34 g/d). Thus, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibition by lovastatin at the therapeutic dose used here did not change the steady-state rate of whole-body cholesterol synthesis. Despite the changes in plasma cholesterol levels, no significant changes were seen in the values of M1, of M3 or of Mtot, the sizes of the pools of rapidly, of slowly, and of total body exchangeable cholesterol. CONCLUSION lovastatin therapy to lower plasma cholesterol does not lead to corresponding reductions in body cholesterol pools or to a reduction in the rate of whole-body cholesterol synthesis. In the new steady state that exists during long-term lovastatin therapy, along with increased expression of the genes for HMG-CoA reductase and the LDL receptor, the body compensates for the effects of the drug so that cholesterol production rate and tissue pool sizes are not changed from pretreatment values.

GALLSTONES PRODUCED EXPERIMENTALLY BY LITHOCHOLIC ACID IN RATS.

Administration of lithocholic acid (1 percent in the diet) consistently produces choledocholithiasis in 8 weeks in rats on an 8-percent protein diet. The gallstones consist predominantly of the calcium salts of free and glycine-conjugated lithocholic and 3α,6β-dihydroxy-5β-cholanic acids. Conjugation of bile acid with taurine can be enhanced and stone formation can be inhibited by an increase in the dietary protein or by a diet supplemented with taurine.

INFLAMMATORY EFFECTS OF PYROGENIC STEROIDS IN ANIMALS.

Summary Three steroid pyrogens known to produce fever and inflammation in man were examined for inflammatory activity in rabbits, guinea pigs, hamsters, rats and dogs. Etiocholanolone, 11-ketopregnanolone and lithocholic acid are all capable of eliciting intense inflammatory reactions in experimental animals, although considerable variation in individual and species sensitivity was observed. Lithocholic acid, like the neutral steroids, failed to produce fever in rabbits, rats, dogs, cats and monkeys, thus confirming the highly specific nature of this activity in humans.

The Significance of Bile Salts Metabolism

A complex system of physical and chemical controls governs the reabsorption processes through which the body seeks to conserve and reuse each bile salt molecule. Particularly important in this system is the balance between nonionized bile acid molecules and ionized bile salts. When the normal circulation of bile salts is disrupted in various clinical syndromes, disturbances in fat metabolism may result.

Diseases of Metabolism.

The fifth edition of Diseases of Metabolism is, like its predecessors, a well-written, easily readable book that will be cordially welcomed and extensively used by students, house staff, and other physicians interested in metabolism and endocrinology. It continues the fine tradition of previous editions and will no doubt enjoy a healthy demand due to its unique treatment of the biochemical aspects of clinical disease. A few chapters have been rewritten by new authors, but the major changes in the present edition (1,513 pages vs 1,073 pages for the