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Title: Alcoholic liver disease : vitamin B6 status
Author: Murray, Raphael James
ISNI:       0000 0001 3436 6340
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1983
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The original purpose of this study was to investigate the clinical importance of nutritional deficiency and genetic markers in the aetiology and morbidity of alcoholic liver disease. Interest in this subject was based on the observation that the onset and severity of alcoholic liver disease was in part dependent on factors other than the period and extent of alcohol abuse. As the principal determinant factors, in addition to alcohol, were considered to be genetic or nutritional a survey of several of these factors in alcoholics was carried out. The genetic factors assessed were acetylator phenotype and alpha-l-anti- trypsin phenotype. The nutritional factors assessed were ascorbate, vitamin B12 and vitamin B6 status. The early results of this study indicated that the value of this approach was limited by the diversity of disease states represented by the term alcoholic liver disease and by the interdependence of the various factors involved. Therefore, it was decided to narrow down the field of research, to concentrate on one area, directly related to the human situation but more amenable to experimentation than the human subject. With a suitable system it would be possible to investigate the effect of specific perturbations under controlled conditions. The alternative approaches considered included investigation of DNA synthesis in liver cell suspensions of biopsy samples, characterisation of the effects of vitamin B6 deficiency in rats fed a vitamin B6 deficient diet and use of PHA stimulated lymphocytes. As the liver cell suspension and vitamin B6 deficient rat studies were unsuccessful it was decided to concentrate on PHA stimulated lymphocyte studies. It was considered that this was an appropriate model system for investigation of cell growth in the alcohol diseased liver, development of a functional assay for vitamin B6 status and characterisation of the effects of vitamin B6 deficiency on DNA synthesis and the effects of vitamin B6 antagonists. Two major advantages of the use of lymphocytes were that they represented a source of cells which under certain conditions might demonstrate the same biochemical abnormalities as other cell types of the same individual and that they would allow assessment of functional vitamin B6 status. As vitamin B6 is the coenzyme of a large number of enzymes in several areas of metabolism, the effect of a vitamin B6 could be expressed in several ways. However, because of the high DNA synthetic requirement in PHA stimulated lymphocytes or in regenerating liver, it was considered that one of the most susceptible enzyme activities might be that of serine hydroxymethyl- transferase, one of several enzymes involved in de novo thymidylate synthesis. Even if a vitamin B6 deficiency did not affect de novo thymidylate synthesis directly, the effect of such a deficiency would still be expressed as a reduction in DNA synthesis. Therefore a principal parameter of interest in this study was the rate of DNA synthesis and the principal method of estimation was based on incorporation of the thymidine analogue (125I)-UdR. To avoid the possible confounding effect of medium pyridoxal on determination of vitamin B6 status, pyridoxal deficient medium was used. Because of the interest in this study on de novo thymidylate synthesis the effects of different medium folate concentrations on cellular adaptation to thymidine utilisation was assessed. To determine whether or not a vitamin B6 deficiency results in a specific restriction of de novo thymidylate synthesis, experiments using the de novo thymidylate synthesis inhibitors MTX and 5-fu were carried out. Several methods were used to determine whether or not PHA stimulated lymphocytes of alcoholic and control subjects differed with respect to functional vitamin B6 status.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine