Reference: Illness

1. Cancer:

© Evolution and Function- A New Perspective on Nutrition Research.
Courtesy of Dr Hoon Tan Dec 2006.

The cytochrome P450 enzymes are widespread in nature and are present in all biological kingdoms. The enzymes are probably the most studied biological system in the past fifty years, due to their capability to catalyse the oxidative metabolism of a wide range of endogenous (originating within an organism) and exogenous (originating outside an organism) compounds. The multiplicity of these enzymes, in respect of the variety of substrates they metabolise, has led to the enzymes being termed mono-oxygenases.

The focal points of current P450 research are the capabilities of these enzymes to biotransform pharmaceutical drugs and to activate procarcinogens to their ultimate carcinogenic species. However, many research groups have failed to address the evolutionary functions of P450 enzymes in terms of their roles in metabolising substrates from the natural world.

It is thought that the ancestral P450 was developed by ancient thermophilic archaebacteria around 3.5 billion years ago (1,2). The evolution of life forms, which has progressed to complex multicellular organisms, presumably has necessitated signalling molecules that control inter- and intracellular communications. Ancestral P450s were expanded to accommodate these new roles, as evidenced by the fact that most of these signalling molecules, including steroid hormones and eicosanoids, are synthesised or partially synthesised by P450s (3).

By 450 million years ago, colonization of land began, first by plants followed by other animal species (4). It is thought that via co-evolutionary events, animals elaborated the P450 system from an endogenous substrate metabolising role to detoxify potentially lethal phytochemicals in the diet (5). This scenario is commonly described as the animal-plant biochemical warfare, which has driven the further evolution of the plants and animals P450 enzymes as plants tried to synthesise phytochemicals as deterrents but herbivores also evolved P450 to detoxify these lethal substances.

The hominids probably started to roam the earth around 15 million years ago but our ancestors did not emerge as species until 1 million years before present. It is possible that during evolution, our body has adapted to utilise exobiotics, in the form of phytochemicals from diet, as part of our exo-hormonal system that helps to maintain homeostasis (inherent tendency in any life forms toward maintenance of physiological and psychological stabilities) in our body. This is evident by the fact that many plant secondary metabolites in our diet do possess properties that can alter animals physiological and biochemical processes. Consequently, this may support the belief of Hippocrates: “Let food be thy medicine and medicine be thy food”.

It is not surprising that man-made chemicals, such as drugs and environment pollutants, are also metabolised by P450s due to their close resemblance to molecules from nature. Elucidation of the natural substrates for each P450 is therefore of paramount importance and may lead to a better understanding of the biochemistry and molecular pharmacology of life.

2. How Cancer Begins:

All of our cells have similar structures and share a majority of their functions.

• Cancers may be categorized into five basic types based on the cell of origin:

• Carcinoma - epithelial cells
• Sarcoma - muscle, bone, cartilage, fat, or connective tissue
• Leukemia - blood cells or their precursors
• Lymphoma - bone marrow derived cells; cancer affects the lymphatic system
• Myeloma - specific blood cells; B lymphocytes (B-cells)

Stages of Tumour Progression

• Tumours typically progress is a stepwise fashion:

• Hyperplasia - cells divide too much but appear normal
• Dysplasia - the tumour cells and tissue appear abnormal
• Carcinoma in situ - tumour contains primarily altered cells and is growing larger; it has not left the site of origin
• Malignant Cancer - tumour has begun to invade nearby or distant tissues

• Benign tumours remain in their initial location and do not invade other tissues.

Initiators and Promoters

• Initiation is the first step in the two-stage model of cancer development.
• Initiators cause irreversible changes (mutations) to DNA that increase cancer risk.
• Promotion is the second step in the two-stage model of cancer development.
• Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters.
• Promoters increase the proliferation of cells and there are two main types:

• Specific - interact with receptors on or in particular target cells.
• Nonspecific - alter gene expression without the presence of a known receptor

Carcinogens

• Substances which can cause cancer are known as carcinogens.
• The process of cancer development is called carcinogenesis.
• Certain carcinogenic chemicals are associated with an increased risk of specific cancers due to chronic exposure.
• One of the most potent carcinogens in humans is benzo[a]pyrene, a compound found in cigarette smoke.

Viruses and Bacteria

• Certain viruses and bacteria have also been associated with the initiation and promotion of tumour growth.
• Some viruses cause cancer directly by affecting cell division while other viruses cause cancer by causing chronic inflammation or reducing immune system function.

Chronic Inflammation

• Chronic inflammation is an important factor in tumour development.
• Inflammation can lead to altered behaviour of cells, stimulation of blood vessel growth (angiogenesis) and tissue remodelling.
• Markers of inflammation correlate with a worse prognosis for cancer patients.

2. Cancer Genes:

The cell division process is dependent on a tightly controlled sequence of events. These events are dependent on the proper levels of transcription and translation of certain genes. When this process does not occur properly, unregulated cell growth may be the end result. Of the 30,000 or so genes that are currently thought to exist in the human genome, there is a small subset that seems to be particularly important in the prevention, development, and progression of cancer. These genes have been found to be either malfunctioning or non-functioning in many different kinds of cancer.

The genes that have been identified to date have been categorized into two broad categories, depending on their normal functions in the cell.

• Genes whose protein products stimulate or enhance the division and viability of cells. This first category also includes genes that contribute to tumour growth by inhibiting cell death.
• Genes whose protein products can directly or indirectly prevent cell division or lead to cell death.

The normal versions of genes in the first group are called proto-oncogenes. The mutated or otherwise damaged versions of these genes are called oncogenes.

The genes in the second group are called tumour suppressors.

A proto-oncogene is a gene that has functions to promote cell division. When these genes are mutated they may produce products that promote cell division in an abnormal fashion. Examples of oncogenes include HER2/neu, ras, and src.

A tumour suppressor gene that is found to be mutated in over 50% of cancers of all types. The protein encoded by this gene is a transcription factor that controls entry into the cell division cycle. Many signals about the health of a cell are relayed to the p53 protein. This results in a decision by the cell as to whether or not cell division should occur. If the cell is damaged and can not be repaired, the p53 protein is involved in triggering a chain of events that causes the cell to kill itself in a process termed apoptosis. Cells defective for p53 do not have these controls and tend to divide even when conditions are not favourable. Like all tumour suppressors, the p53 gene is normally involved in slowing or monitoring cell division.

References:
(1)Cleaves, H. J.; Miller, S. L. Oceanic protection of prebiotic organic compounds from UV radiation. Proceedings of the National Academy of Sciences of the United States of America 1998, 95, 7260-7263.
(2)Lewis, D. F. V. Guide to Cytochrome P450- Structure and Function; Taylor & Francis: London and New York, 2001.
(3)Porter, T. D.; Coon, M. J. Cytochrome-P-450 - Multiplicity of Isoforms, Substrates, and Catalytic and Regulatory Mechanisms. Journal of Biological Chemistry 1991, 266, 13469-13472.
(4)Harland, W. B.; Armstrong, R. L.; Craig, L. E.; Smith, A. G.; Smith, D. G. A Geological Time Scale; Cambridge University Press: Cambridge, 1989.
(5)Gonzalez, F. J.; Nebert, D. W. Evolution of the P450-Gene Superfamily - Animal Plant Warfare, Molecular Drive and Human Genetic-Differences in Drug Oxidation. Trends in Genetics 1990, 6, 182-186.