By Hakeem Alexander

(Exercising Your Mind) The purpose of this document is to explore a pharmacogenetic model, and how it may be applied to other areas of biodiversity, epigenetics, nutrigenomics, and toxicology. I have interpreted a pharmacological model and adapted it here to suit my outline. This may lend some insight into possible solutions for many physical disorders and mental illnesses that are biologically based.

A good analogy to keep in mind as you read this would be to imagine sailboats on the ocean. One may be traveling east, one west, and yet another may be idle. The same wind is blowing on them of course, but the difference in direction has to do with the setting of their sails. Likewise, our genes are the factors which set our “sails” or, express our enzymes and other proteins. The same “wind” blows on us all. We live on the same planet, and are exposed to the same elements and chemicals in turn. The different reactions or lack thereof, may be due to the encoding of our genes, and the individual expression of them.

Pharmacogenetics 101

As far as drug metabolism is concerned, we can place them into two (2) categories. These are Active-Drugs and ProDrugs.

Active drugs DO NOT have to be broken down into other compounds to be effective. An example of this is the anticoagulant or blood thinner Coumadin, also known as warfarin sodium.

Prodrugs DO have to be broken down into other compounds to be effective. One such drug is codein, which may be a phosphate or sulfate. Codein breaks down into morphine, which then acts as an analgesic or pain reliever.

The mechanism of metabolism for these drugs in the human body is to be found mainly in the liver. This is known as the Cytochrome P-450 Enzyme System or, CYP450. There is a large number of CYP450 genes, however, only the CYP1, CYP2, and CYP3 enzyme families play a major role in metabolizing drugs. More specifically, it is the CYP2D6 that I am discussing here. The number 2 is the gene family, the letter D is the gene subfamily, and the number 6 is the specific gene number.

There are prominent interethnic differences in the frequency and distribution of variant alleles. Genetic polymorphisms have been identified in the genes encoding all the main CYP450s responsible for drug and other xenobiotic or, foreign substance metabolism. Around 60 active human CYP450 genes are known, and most of these genes are polymorphic. A large number of pharmacologic agents are metabolized by about 10 CYP450s in human beings. A significant number of adverse drug reactions are due to the polymorphic forms of the CYP450s, and may also contribute to drug response.

A polymorphism is a genetic variant that appears in at least 1% of the population. One example is the human ABO blood groups. Polymorphism is similarly used here to denote that a certain gene sequence or genotype, may produce a slightly or radically different protein / enzyme phenotype. The difference may be in its amino acid structure, shape or size. As it applies here, the CYP2D6 Enzyme System may be genotypically the same, but may vary in phenotypic expression significantly enough to result in absence or reduced level of activity.

A Pharmacogenetic Model

Because of biodiversity and genetic polymorphisms, people metabolize these xenobiotic substances differently from each other when the standard dose is administered. Four general categories may be applied to describe the functional consequences of such variations. These are Extensive-Metabolizers, Intermediate- or Slow-Metabolizers, Poor-Metabolizers, and Ultra-Metabolizers.

Extensive-metabolizers break down and eliminate both active-drugs and prodrugs efficiently, and are said to have a normal therapeutic response in the individual with this metabolism.

Slow-metabolizers perform somewhat like poor-metabolizers but not as inefficiently, and may have similar reactions. This is why they are also known as Intermediate-metabolizers, because they are between extensive and poor. (Intermediate)

Poor-metabolizers may eliminate active-drugs too slowly and therefore may cause a build-up, which may lead to toxicity or overdose. With pro-drugs, they may not break it down quickly enough before it is excreted and may have little or no effect at all.

Ultra-metabolizers reverse the action of poor-metabolizers, and may eliminate active-drugs too quickly for them to be effective, and may show little to no effect at all. When it comes to pro-drugs, the compound may be broken down more rapidly than it is excreted, and may cause a build-up resulting in toxic or overdose reaction. (ultra-rapid)

Figure 1.


Applications of the pharmacogenetic model beyond pharmacology.

The above outlined pharmacogenetic model, may be applied to many other chemical and biological processes. Besides pharmaceuticals, there are a wide range of man-made, xenobiotic products that humans are exposed to every day. These include motor vehicle exhaust, pesticides and herbicides from agriculture, fluoride in water, mercury amalgam tooth fillings, body-care products like aluminum in deodorant, processed food-stuffs like high-fructose corn syrup (HFCS), hydrogenated oils, monosodium glutamate (MSG), food-dyes like tartrazine or yellow #5, genetically modified organisms (GMOs), irradiated foods, and Bisphenol-A(BPA) which is a contaminant found in plastic bottles and other plastic containers.

Nutrigenomics
In addition, humans also react very differently to natural foods and their products, and other naturally occurring elements from nature. These may also be categorized as Active-Compounds or Pro-Compounds as many substances entering the body will either be left as they are or, broken down into other constituents. The same metabolic categories of Extensive, Poor and Ultra will be applied here as well, because these same products must be eliminated, and this rate will vary. As with the drugs, this may result in toxicity (i.e., hypervitaminosis), or in some cases a lack of proper nutrient absorption.

These genetic differences may explain why a group of people may be exposed to the same chemicals, but only a few will develop any adverse reactions to them. This may also be able to explain the meteoric rise in obesity, diabetes, autism, Alzheimer’s and other diseases. While one person may be an extensive metabolizer of fluoride and have no problems, that same person may be a poor metabolizer of Bisphenol-A and react unfavorably. The reverse could be true for someone else who is tolerant of Bisphenol-A, but reacts adversely to fluoride. In effect, the more man-made products we are exposed to, the more likely we are to be poor metabolizers of some of them, if not most.

The basic implication is that increasing man-made pollution, is the major cause of the increasing disease on this planet for individuals and environmentally. The proposed solution is to develop biocompatible technology, that is able to be eliminated metabolically and biodegradable at a rate that exceeds toxic accumulation. The most reasonable way to do this, would be to rely more on plant based compounds that are harvested and extracted using eco-friendly methods.

The most significant problem with a great deal of new technology, is that many of these new substances are not as`rigorously tested as drugs are, if at all. They are also not properly labeled, therefore, no accurate m
easurements can be made as to their potential consequences, whether they be beneficial or detrimental.

It would be most useful to see how these materials impact upon human metabolism. Close examination through a simple action such as more accurate labeling, would be insightful. To which substances do we react adversely? How do we epigenetically adapt through increased or decreased gene expression to others? What is the level of mutagenesis, if any?

What I have explored here is a method for analyzing biological interactions based on genetic diversity. It is an interpretation and expansion of a pharmacogenetic model. its usefulness is that it may help to explain the different reactions that we all have to the same stimuli.

Using a model similar to the Food Awareness Subjective Testing (F.A.S.T.) outline I have published
(https://eym.hypnoathletics.com/2008/04/13/food-awareness-subjective-testing-f-a-s-t-outline/), I will be expanding on this idea of pharmacogenetics to develop therapeutic applications to be integrated into nutrition counseling for fitness training and general wellness. More importantly, I will work to integrate this into a model for Sustainable and Biocompatable living.