Absorption and Utilization of Amino Acids

Volume III

Mendel Friedman

• Publisher: CRC Press
• Year: 2018
• Print ISBN: 9781315890340
• eBook ISBN: 9781351086349
• Topic: Medicine
• Subtopic: Biochemistry in Medicine

Containing 45 papers written by outstanding international authors from 14 countries, this three-volume compendium brings together the elements needed to understand the factors which influence the utilization of amino acids. The wide-ranging topics include descriptions of metabolic pathways and mechanisms of the biological utilization of amino acids, as well as factors that influence amino acid bioavailability in enteral and parenteral nutrition. The use of amino acids to improve the quality and safety of the diet is presented. Also discussed are amino acid precursors of biogenic amines and the role of amino acids in atherosclerosis, cancer, and immunity. Scientists from many disciplines will benefit from this broad overview.

Chapter 1

ALTERED METHIONINE METABOLISM AND UNBALANCED TRANSMETHYLATION: A POSSIBLE BASIS FOR THE DYNAMIC PHENOTYPE OF CANCER

Robert M. Hoffman

TABLE OF CONTENTS

I.	Phenotypic Characteristics of Cancer
II.	Can Somatic Mutation Account for the Cancer Phenotype?
III.	Altered DNA Methylation and Cancer
IV.	Unbalanced Global Methylation and Cancer: Methionine Dependence
V.	Conclusions
VI.	Summary
Acknowledgments
References

I. PHENOTYPIC CHARACTERISTICS OF CANCER

Cancer is due to many cellular changes. The transformation of a normal cell into a metastasizing cancer involves changes in cellular growth control, in the way cells interact with their neighbors, and in biochemical pathways. Cancer cells can acquire the ability to leave their original site, migrate through the circulatory or lymphatic system, and implant and grow in tissues radically different from that of their origin, often losing many of their differentiated properties in the process. One can postulate from this information that the cellular changes in cancer are global, involving a great many cellular reactions and genes. Not only have the cells within a tumor undergone significant changes, but they continue to do so. The tumor is a continually evolving system, often producing different cell types whose relative numbers are in flux. Therefore, to explain the mechanism of cancer, one must describe means by which cells undergo initial transformation and then other changes in many processes giving rise to tumors which are continually evolving.

Besides the evidence that phenotypic changes in cancer reflect a great number of changes in the cell, studies at the level of RNA transcription have also indicated large programmatic changes occurring in cancer. For example, Groudine and Weintraub¹ have indicated that oncogenic transformation of chick embryo fibroblasts by Rous sarcoma virus results in accumulation of RNA from approximately 1000 average-size new transcription units. Hanania, et al.² have identified 2500 to 3000 distinct transcription units they term tumor-specific. These transcripts were found to occur, specifically in human lymphoid neoplasias, and not to occur in normal lymphoid cells, including a cell line immortalized by Epstein-Barr virus. Further study indicated that these transcripts occur in all human neoplasias they studied, including cell lines derived from leukemias, malignant lymphomas, sarcomas, and leukemic cells and in solid tumors taken directly from patients. The tumor-specific transcripts were not found in or found in only minor amounts in normal human lymphoid cells or fibroblasts grown in culture, fetal, and chorio-placental tissues. Other studies have indicated many new genes activated in tumors.^3,4

II. CAN SOMATIC MUTATION ACCOUNT FOR THE CANCER PHENOTYPE?

The question arises whether the current theories of somatic mutation⁵ (especially in somatic mutation of cellular oncogenes, the approximately 50 genes found in cells that correspond to the transforming genes of retroviruses), are sufficient to describe the changes leading to human cancer. It is difficult to explain the large programmatic changes occurring in cancer and the accompanying large numbers of new genes transcribed in cancer by the somatic mutation hypothesis. One would have to postulate enormous numbers of mutations in cancer, or at least a rather large number of mutations in regulatory genes. One would also have to explain the continuing phenotypic variability that seems to be a common feature of all cancers. However, studies have indicated that cancer cells have no higher mutation frequency than do normal cells.⁶ Surveys in human cancers that look for mutations in the ras^H proto-oncogene, for example, have found either none,⁷ or very few.^{8, 9, 10} However, it has been estimated that the rate of metastatic variation in cancer cells may be two orders of magnitude higher than the mutation rate in these cells.^{11, 12, 13}

III. ALTERED DNA METHYLATION AND CANCER

What sort of hypothesis can explain the multiple phenotypic changes continually occurring in cancer? Possible solutions to the problem, at least in part, come from studies in methionine metabolism and transmethylation in cancer. DNA methylation seems to have an important effect on the program of gene expression.¹⁴ For example, the sites of undermethylation in sperm DNA correspond to location of regions of altered chromatin structure in somatic tissues which result in constitutive gene expression, as revealed by regions of hypersensitivity to nucleases.¹⁴ More direct experimentation indicates that in vitro methylation of DNA can silence genes when they are assayed in vivo and, conversely, agents which inhibit DNA methylation can activate many genes. Thus, it can be seen when DNA methylation is disrupted, major changes in cellular programming may take place that could result in on-cogenic changes.¹⁵ Indeed, in a number of surveys of DNA methylation in cancer, results have shown the DNA is highly hypomethylated.^{16, 17, 18, 19, 20, 21} Even precancerous cell types such as benign polyps of the human colon have been found to have DNA that is hypomethylated, demonstrating that defective DNA methylation may be an early event in oncogenesis.²¹ The changes in the degree of hypomethylation in cancer may be quite large. Studies have indicated that in some cancer cell types at least, half the methyl groups in DNA may have been lost.¹⁷ These losses in methyl groups in DNA, which may function in the silencing of genes including oncogenes^22,23 may, therefore, allow large sets of genes to become activated, thereby allowing at least some of the major changes of oncogenic transformation to occur.

However, the situation is not so simple in that a number of studies have demonstrated that cancer cells may have an increase in DNA methylation. For example, Baylin et al.²⁴ have found that in small-cell lung carcinomas and lymphomas, the 5′-region of the calcitonin gene exhibits methylation of increased numbers of CCGG sites in comparison with normal tissues. Some cancer cells may have an overall increment in DNA methylation.²² Chandler et al.²⁵ however, demonstrate a possibly more important point in their investigations of individual genes in cancer cells, such as the ras^H proto-oncogene, where they observe a striking heterogeneity in the methylation pattern. Their data suggest a relaxation of the normal mechanisms responsible for stable methylation patterns. The instability of cancer DNA methylation may in part be explained by the elevated levels of DNA methyltransferase found in cancer cells.²⁶ These observations in toto indeed suggest that cancer cell DNA methylation is unbalanced and possibly continually changing which is consistent with the large programmatic alterations continually occurring in cancer cells.²⁷

IV. UNBALANCED GLOBAL METHYLATION AND CANCER: METHIONIN...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Chapter 1 Altered Methionine Metabolism and Unbalanced Methylation: A Possible Basis for the Dynamic Phenotype of Cancer
• Chapter 2 Determination of Histidine, 1-Methylhistidine and 3-Methylhistidine in Biological Samples by HPLC; Clinical Application of Urinary 3-Methylhistidine in Evaluating the Muscle Protein Breakdown in Uremic Patients
• Chapter 3 Role of Glutathione and N-Acetylcysteine as Inhibitors of Mutagenesis and Carcinogenesis
• Chapter 4 Dietary Amino Acids, Eating Behavior, and Trichothecene Mycotoxicoses
• Chapter 5 Amino Acid Precursors of Biogenic Amines
• Chapter 6 Absorption and Metabolism of Heated Protein-Carbohydrate Mixtures in Humans
• Chapter 7 Effect of Heat on Tryptophan in Food: Chemistry, Toxicology, and Nutritional Consequences
• Chapter 8 Methods for Determining Bioavailability of Amino Acids for Poultry
• Chapter 9 Kinetics of Protein Degradation in the Rumen
• Chapter 10 Transport of Nitrogenous Compounds by the Gastrointestinal Tract
• Chapter 11 The Utilization of Free and Protein-Bound Lysine
• Chapter 12 Rumen Protected Amino Acids in Ruminant Nutrition
• Chapter 13 Amino Acid Digestibility in Pigs as Affected by Diet Composition
• Chapter 14 Considerations in Methodology for the Determination of Amino Acid Digestibilities in Feedstuffs for Pigs
• Chapter 15 A Comparison of In Vitro Enzymatic and Rat Balance Methods for Measuring Digestibility of Protein and Amino Acids in Foods
• Chapter 16 The Resistance to Proteolytic Breakdown of Some Plant (Seed) Proteins and Their Effects on Nutrient Utilization and Gut Metabolism
• Chapter 17 Chemistry and Analysis of Amino Acids
• Index