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C-10(19) Oxidation of Vitamin D by Anaerobic Gastrointestinal Bacteria Robert Marshall Gardner Iowa State University

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C-10(19) Oxidation of Vitamin D by Anaerobic Gastrointestinal Bacteria Robert Marshall Gardner Iowa State University Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1985 C-10(19) oxidation of vitamin D by anaerobic gastrointestinal bacteria Robert Marshall Gardner Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Microbiology Commons Recommended Citation Gardner, Robert Marshall, "C-10(19) oxidation of vitamin D by anaerobic gastrointestinal bacteria " (1985). Retrospective Theses and Dissertations. 7849. https://lib.dr.iastate.edu/rtd/7849 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quahty of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure complete continuity. 2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed. For blurred pages, a good image of the page can be found in the adjacent frame. If copyrighted materials were deleted, a target note will appear listing the pages in the adjacent frame. 3. When a map, drawing or chart, etc., is part of the material being photographed, a definite method of "sectioning" the material has been followed. It is customary to begin filming at the upper left hand comer of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again—beginning below the first row and continuing on until complete. 4. For illustrations that cannot be satisfactorily reproduced by xerographic means, photographic prints can be purchased at additional cost and inserted into your xerographic copy. These prints are available upon request from the Dissertations Customer Services Department. 5. Some pages in any document may have indistinct print. In all cases the best available copy has been filmed. University Microfilms Intemationcil 300 N. Zeeb Road Ann Arbor, Ml 48106 8514401 Gardner, Robert Marshall C-10(19) OXIDATION OF VITAMIN D BY ANAEROBIC GASTROINTESTINAL BACTERIA Iowa State University PH.D. 1985 University Microfilms Intsmstionsl 300 N. Zeeb Road, Ann Arbor, Ml 48106 C—10(19) oxidation of vitamin D by anaerobic gastrointestinal bacteria by Robert Marshall Gardner A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Departments: Microbiology Animal Science Co-majors: Microbiology Nutritional Physiology Approved; Members of the Committee: Signature was redacted for privacy. Signature was redacted for privacy. In Charge of Maior Work Signature was redacted for privacy. Signature was redacted for privacy. Iowa State University Ames, Iowa 1985 ii TABLE OF CONTENTS Page GENERAL INTRODUCTION 1 Dissertation Format 2 LITERATURE REVIEW 3 Bacterial Transformations of Steroids in the Gastrointestinal (GI) Tract 3 Importance and implications 3 Bile 6 Cholesterol 23 Other biologically important steroids 28 Vitamin D 33 Vitamin D 35 Importance and implications 35 Metabolism 38 Biological activity 41 Enterohepatic cycling of vitamin D 42 Requirements and toxicity 43 SECTION I. FACTORS AFFECTING THE PRODUCTION OF 5(E) 19-NOR-lO-KETO-VITAMIN D3 BY RUMEN BACTERIA 46 INTRODUCTION 47 MATERIALS AND METHODS 49 General 49 Steroids 49 Enzymes 50 Extraction and Chromatography 50 Preparation of Media 51 Assay Conditions 52 iii Rumen Fluid Studies 52 Oxygen studies 53 Preincubation treatments 53 Mixed Culture Studies 53 Filtration 54 Time study 54 Glucose inhibition 55 Isolation of Clostridium sp. Strain A264 55 Pure Culture Studies 55 Glucose inhibition studies 56 Cysteine Studies 56 RESULTS 57 Rumen Fluid Studies 57 BHI Broth Culture Studies 58 DISCUSSION 62 LITERATURE CITED 77 SECTION II. THE BIOLOGICAL ASSESSMENT OF VITAMIN Dg METABOLITES PRODUCED BY RUMEN BACTERIA 80 INTRODUCTION 81 MATERIALS AND METHODS 83 General 83 Sterols 83 Isolation of lO-Keto-Dg From Bovine Plasma 84 Radioligand Binding Assays 85 Pharmacokinetics 85 iv Biological Evaluation 86 Preparation "of Bacterial Culture Medium 87 Isolation of Clostridium sp. Strain A264 87 Rumen Fluid 87 Assay Conditions 88 Extraction and Chromatography 89 RESULTS 91 Isolation and Mass Spectral Detection of lO-Keto-Dg From Calves 91 Pharmacokinetics 91 Biological Activity Evaluation 92 Relative Affinity for Plasma Vitamin D Binding Protein 93 Relative Affinity for Thymus 1,25-(OH)2-Vitamin D3 Receptor Protein 93 Characterization of "Peak A" 93 DISCUSSION 96 LITERATURE CITED 114 SUMMARY AND DISCUSSION 117 LITERATURE CITED 119 ACKNOWLEDGMENTS 133 1 GENERAL INTRODUCTION The ability of gut bacteria to structurally modify steroids has important ramifications. Slight structural changes can dramatically affect function or biological activity. Previous research on bacterial steroid biotransformations has primarily dealt with the three major classes of steroids which pass through the gastrointestinal tract: cholesterol, steroid hormones, and bile acids. Recently, vitamin D3 (a 9,10 seco-steroid) has been shown to undergo bacterial-catalyzed C-10(19) oxidation, yielding the major product 5(E)-19-nor-10-keto- vitamin D3 (lO-keto-Da). This compound has also been detected in the plasma of cows receiving large oral doses of vitamin D3, thus denoting in vivo production. Biological assays with lO-keto-Dg revealed that the C-10(19) oxidative pathway represents a deactivation process in vitamin D me­ tabolism. Whether or not the vitamin D status of an animal is affected by the bacterial removal of vitamin D has yet to be determined. The production of lO-keto-Ds could also be an important process in monogastric animals since vitamin D3, 25-hydroxyvitamin D3, and 1,25- dihydroxyvitamin D3 circulated in the enterohepatic cycle. In addition to this cycle, diet represents the other major route by which vitamin D enters the gut. Results obtained from ruminai systems should also transfer to monogastric animals since the rumen is a model of study for the microbiology of the cecum and large intestine. In light of current trends of providing large oral doses of vitamin D for domestic animals 2 in feeds, or administered clinically, a great deal of substrate may be available for the metabolism of vitamin D by gut bacteria. Therefore, the first phase of this study involves defining the conditions necessary for bacterial C-10(19) oxidative metabolism to occur. It is hoped that this work will help to clarify the situation in vivo. The second part reports the isolation, purification, and bio­ logical assessment of lO-keto-Dg and "Peak A," a new bacterial metabo­ lite of vitamin Dg. Dissertation Format This dissertation is presented in the alternate thesis format, and includes two manuscripts to be submitted for publication in (1) Applied and Environmental Microbiology, and in (2) Biochemical and Biophysical Research Communications. The format used in this dissertation is that of the American Society for Microbiology. An in-depth literature re­ view precedes the first manuscript. At the end of each section, a sep­ arate literature cited section has been included to facilitate publica­ tion. A general summary and discussion follow the final manuscript. The doctoral candidate, Robert Marshall Gardner, was the principal investigator in each of these studies, with the exception of the pharmacokinetics and binding assays which were performed by R. L. Horst. 3 LITERATURE REVIEW This literature review is divided into two major sections. Part I will deal with bacterial biotransformation of steroids in the gastro­ intestinal tract; Part II contains a summary of selected literature on the vitamin D-endocrine system. Bacterial Transformations of Steroids in the Gastrointestinal (GI) Tract Importance and implications Anaerobic bacteria in the GI tract play an important role in al­ tering the structure of many endogenous and dietary steroids (38, 41, 89). Certain structural modifications of the parent steroid can impart unique biological activity, or inhibit inherent activity, resulting in important physiological changes in the host. Both situations should be considered when steroids are administered orally (2, 14, 28) or if they undergo enterohepatic circulation (8). These biologically altered com­ pounds, in many instances, can be reabsorbed back into the body, either directly through the cell membranes of the intestinal epithelium or by the enterohepatic cycle (30, 38, 89). After absorption, further modi­ fication of the steroid may occur in the liver (89). Research with steroid biotransformations by intestinal bacteria has emphasized
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