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Pyrogenic and Inflammatory Properties of Certain Bile Acids in Man

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Pyrogenic and Inflammatory Properties of Certain Bile Acids in Man PYROGENIC AND INFLAMMATORY PROPERTIES OF CERTAIN BILE ACIDS IN MAN Robert H. Palmer, … , Paul B. Glickman, Attallah Kappas J Clin Invest. 1962;41(8):1573-1577. https://doi.org/10.1172/JCI104614. Research Article Find the latest version: https://jci.me/104614/pdf Journal of Clinical Investigation Vol. 41, No. 8, 1962 PYROGENIC AND INFLAMMATORY PROPERTIES OF CERTAIN BILE ACIDS IN MAN * By ROBERT H. PALMER, PAUL B. GLICKMAN AND ATTALLAH KAPPAS (Fronm the Department of Medicine and the Argonne Cancer Research Hospital,t The University of Chicago, Chicago, Ill.) (Submitted for publication January 25, 1962; accepted March 23, 1962) This is a report on the pyrogenic and inflam- Local inflammatory reactions were regularly observed matory properties of certain bile acids in man. after injection of lithocholic acid. The onset of inflam- The study was prompted by the structural simi- mation, characterized by the usual physical signs, was variable, ranging from 6 to 30 hours after injection. The larity between these acidic steroids and the pyro- inflammation usually increased for 2 to 3 days and then genic neutral steroids described previously (2-7). gradually regressed, with an indolent course sometimes In addition, it seemed important to establish lasting 2 to 4 weeks. Histologically, biopsies of injection whether the large quantities of steroid acids formed sites showed edema and necrosis of tissue, with a marked during the metabolism of cholesterol could serve polymorphonuclear infiltrate. Further details will form the basis of a subsequent report. A photomicrograph of as a source of endogenous compounds having fe- a biopsy taken 4 days after injection is shown in Figure 2. ver-producing action in man. It is of interest that the period of most intense inflamma- tion usually occurred well after the fever had subsided. METHODS AND RESULTS Constitutional symptoms such as headache, malaise, Nineteen bile acids and derivatives were examined for nausea, anorexia, and so forth, were intense, and patients fever-producing activity after their intramuscular ad- frequently complained of an unusually strong sense of ministration to adult volunteer hospital patients. Litho- fatigue. Myalgias and arthralgias were less frequent cholic acid was repeatedly recrystallized to insure purity. than those observed after injections of neutral steroid The glycine, taurine, and acetyl derivatives of lithocholic pyrogen. acid were synthesized and purified in these laboratories; 2. 3-Acetyl lithocholic acid. This compound was ad- the other compounds were obtained commercially and ministered to four subjects in single doses of 25 mg each. used without additional purification. All bile acids were All developed intense pyrogenic reactions, although in dissolved in propylene glycol, in concentrations of 12.5 one the onset of fever was delayed until the day after and 25.0 mg per ml, and because of their acidity these inj ection. Inflammatory reactions and constitutional solutions were neutralized with dilute base. The general symptoms were comparable to those produced by litho- details of the study, including precautions taken to ex- cholic acid. clude bacterial pyrogen contamination, were similar to 3. 24-Methyl lithocholic acid. One subject received those described in a previous report (3). The com- 25 mg and two received 12 mg each. All developed in- pounds examined, together with the incidence of pyro- tense pyrogenic responses, the larger dose causing a pro- genic responses which followed their injection, are listed longed fever lasting 5 days. Inflammatory reactions and below. constitutional symptoms were correspondingly severe. 1. Lithocholic acid (3a-hydroxycholanic acid). Nine- Because of the intensity of these responses, no further teen subjects received 22 intramuscular injections of 6 to testing was done. 50 mg each. Pyrogenic responses at different doses were 4. Glycolithocholic acid. Five subjects received 12 mg as follows: 6 mg, 5 of 5; 12 mg, 6 of 7; 25 mg, 7 of 8; and four received 25 mg each. In addition, two other 50 mg, 1 of 2. In general, pyrogenic reactions were simi- subjects received 21 mg each, the steroid solution having lar to those previously described with neutral steroid been sterilized by Seitz filtration rather than by auto- pyrogens and the responses of three subjects to injection claving. All subjects, except one, developed pyrogenic of 6 mg of this bile acid are shown in Figure 1. At this and inflammatory reactions similar to those obtained with small dose, lithocholic acid appeared to be more intensely unconjugated lithocholic acid. The single subject who pyrogenic than either etiocholanolone or pregnanolone did not develop a fever after receiving an injection of 12 (4, 6). mg, did develop a 2 X 2 cm area of inflammation at the * Presented in part before the American Society for site of injection. Chromatographic analysis of the glyco- Clinical Investigation, May 1, 1961, and published in ab- lithocholic acid used in these injections showed it to be stract form (1). This study was supported in part by the free of unconjugated precursor. Joseph and Helen Regenstein Foundation. 5. Taurolithocholic acid. Six subjects received 12 mg t Operated by the University of Chicago for the United and four received 25 mg each. The maximum tempera- States Atomic Energy Commission. ture reached in the group receiving 12 mg was 38.30 C 1573 1574 ROBERT H. PALMER, PAUL B. GLICKMAN AND ATTALLAH KAPPAS BILE ACID FEVER IN MAN In addition to the consistent development of intense in- flammatory reactions, unaccompanied by fever, most sub- LITHOCHOLIC ACID 6 MG. I.M. jects receiving taurolithocholic acid complained of marked constitutional anorexia a 401 symptoms, especially and strong sense of fatigue. 6 6. W) Hyodeoxycholic acid (3a,6a-dihydroxycholanic acid). ia Five ab, subjects received 100 mg each. One developed a w11 marked febrile two 0 response, developed low grade but sig- nificant fevers, and two subjects had no febrile responses. 1 7. Ursodeoxycholic acid (3a,7#-dihydroxycholanic acid). ICla This compound was tested in nine in amounts of I- subjects 9 100 each. One wIC mg subject developed a moderately in- a a tense fever, three responded with small but significant I- temperature rises, and five showed no temperature ele- 37 vations. Despite several pyrogenic reactions among the sub- 0 2 4 a 20 22 6 10 12 14 16 Is jects receiving these last two compounds, no inflamma- HOURS AFTER INJECTION tory reactions were noted grossly and none of the sub- FIG. 1. FEBRILE RESPONSES OF THREE SUBJECTS TO THE jects complained of local tenderness. However, three INTRAMUSCULAR INJECTION OF 6 MG OF LITHOCHOLIC subjects (two of whom remained afebrile) complained of ACID. some of the previously described constitutional symptoms after injection of ursodeoxycholic acid. (one subject), and in the group receiving 25 mg, 380 C 8. The following twelve compounds were (one subject). All other patients nonpyrogenic remained afebrile when tested in at least six subjects in doses of 100 mg despite the presence in all of intense local inflammatory each: 7-ketolithocholic acid (3a-hydroxy-7-ketocholanic reactions which were frequently as severe as those pro- acid); 3,6 diketocholanic acid; chenodeoxycholic acid duced by glycolithocholic or lithocholic acids. Because (3a,7a-dihydroxycholanic acid) ; deoxycholic acid (3a,12a- of the severity of these reactions, no attempt was made to dihydroxycholanic acid); apocholic acid (3a,12a-dihy- elicit fever with doses greater than 25 mg. Figure 3 droxy-A8-14-cholenic acid); diketolithocholic acid (3a-hy- shows a biopsy of one reaction to an injection of 25 mg droxy-7,12-diketocholanic acid); dehydrocholic acid (3,7,- together with the corresponding temperature record. 12-triketocholanic acid); cholic acid (3a,7a,12a-trihy- FIG. 2. ACUTE INFLAMMATORY REACTION AFTER THE INTRAMUSCULAR INJECTION OF LITHOCOLIC ACID. (X 245) BILE ACID FEVER 1575 U) (I IaJw C-TAURINE 391~ 0 w a HO' 381* I- w 0. bJ -~~~~~~ I- 37 F 0 2 4 6 8 10 12 14 16 18 20 22 HOURS AFTER INJECTION FIG. 3. ACUTE INFLAMMATORY REACTION AFTER THE INTRAMUSCULAR INJECTION OF 25 MG OF TAUROLITHOCHOLIC ACID IN THE ABSENCE OF ANY FEBRILE RESPONSE. (x 290) droxycholanic acid); glycocholic acid; taurocholic acid; in a manner previously demonstrated for the neu- and lithobilianic acid. tral steroid pyrogen, etiocholanolone (8, 9). The Among these patients were there scattered instances of of lithocholic acid and its mild temperature elevations (or absence of normal noc- activity conjugates dem- turnal temperature depressions), but these did not form onstrated in this study makes these monohydroxy a consistent pattern and were not considered significant. compounds of special interest in this regard, al- In addition, no inflammatory reactions or constitutional though these substances may prove to be only the symptoms developed after injection of these steroids. most potent of a series of pharmacologically ac- tive related steroids. DISCUSSION The origin of lithocholic acid and its derivatives The pyrogenic neutral steroid hormone metab- and their concentrations in tissues, fluids, and in- olites described previously belong to the 5,8-H testinal contents are not well known. However, series of compounds, in which the hydrogen atom approximately 1,000 mg of cholesterol is degraded projects in front of the plane of the nucleus, and to bile acids daily (10, 11). During this process, the A: B ring junction is angular (cis). This mo- hydroxylation of the nucleus occurs, first at car- lecular configuration also characterizes the bile bon 7 and then at carbon 12, resulting in the two acids, which represent the principal steroid end principal bile acids in man, chenodeoxycholic and products of cholesterol metabolism. The large cholic acids. Lithocholic acid could be formed amounts of these steroid acids formed daily from either by failure of C-7 hydroxylation initially or the breakdown of cholesterol thus represent a large through subsequent bacterial dehydroxylation in potential source of endogenous fever-producing the intestine.
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