**1. Introduction**

The history of genetic variations in drug responses can be traced to the 1950s with the observations that muscle relaxant suxamethonium chloride and drugs metabolized by Nacetyl transferase exhibit differences in response in patients. One in 3500 caucasians was found to possess the less efficient variant of the enzyme, butyryl chlolinesterase that metabolizes suxamethonium chloride; an anaesthetic agent.As a consequence, the drug's effect is prolonged with slower recovery from surgical paralysis.

The term pharmacogenetics evolved from the combination of two areas of study namely pharmacology and genetics. Pharmacology is the study of how drugs work in the body and genetics is the study of how characteristics that result from the action of genes acting together are inherited and how they function in the cells of the body . Therefore, pharmacogenetics refers to genetic differences in metabolic pathways which can affect individual responses to drugs both in terms of therapy and adverse effects. Pharmacogenetics helps our understanding of why some individuals respond to drugs and others do not and why some require higher or lower doses to achieve optimal therapeutic responses.

In addition, pharmacogenetic information helps the physician to identify those patients who will respond favourably to therapy or develop side effects.

A recent offshoot of pharmacogenetics, termed pharmacogenomics is the study of drug response in the context of the entire genome. Pharmacogenomics facilitates information on variations in all the genes in a group of individuals simultaneously to determine the basis of variants in drug response. It is therefore not uncommon to find the two being used interchangeably.However for the purpose of this chapter, pharmacogenetics will be the focus.

Individual variation in response to drug ranges from failure to respond to drug therapy to drug to drug interactions when several drugs are taken simultaneously. The clinical consequences range from patients' discomfort through serious clinical illness to the occasional fatality. Approximately 7% of patients are affected by adverse drug reactions, increasing the overall hospital costs by 19% and drug costs by 15%. Some 0.3% of adverse drug reactions have fatal outcome (Topic 2010).

#### **1.1 Individual variation in drug effects**

Variation in drug metabolism and drug response among individuals of the same body weight and on the same drug dose can be due to temporary causes such as transient enzyme

Pharmacogenetics: The Scientific Basis 181

Adverse drug reactions are thought to kill many hospitalized patients worldwide. In the US alone, the estimate of deaths attributable to drug reactions is about 100,000 annually and it is believed that many of these reactions are due to genetic variations. Thus many deaths are avoidable if genetic testing or genomic information of patients are available and utilized

Pharmacogenetics will therefore permit gene profiling to answer questions about drug responses and promote the design of better and safer drugs. In addition, individualized dosing has the potential of better therapeutic outcome. Therefore pharmacogenetics is expected to revolutionise drug dosing and therapy .However, there are still many challenges to overcome. These include cost implications, standardization , quality control of testing, and relevance of biomarkers and tests. Nevertheless, the advent of pharmacogenetics and establishment of guidelines by regulatory bodies like Food and Drugs Administration (FDA) European Medicines Agency (EMEA) and American Association of Clinical Chemists (AACC) are

The understanding that drug response may be multifactoral helps us to recognize the importance of examining more than the classical "single gene-single protein concept which gave birth to pharmacogenomics. In addition, there are more evidences that modifications besides outright mutation of genes, for example, methylation of promoter region by epigenetic factor impact gene expression and drug responses. Moreover, genotype is not the only determinant of phenotype. For example, individuals whose genotypes falls extensive metabolizers via CYP2D6 can display a phenotype that would characterize them as poor metabolizers if they are co-administered low doses of quinidine which is a potent inhibitor of CYP2D6 . Therefore, differences in phenotype does not necessarily translate into difference in pharmacologic response between subjects. In the same fashion, mutation of the genes may not

Because of significant racial differences in genetic composition, it is important that caution is exercised in the interpretation of genetic testing. For example different genotypes may give rise to the same phenotype.In addition, there are varieties of mutations in NAT2 that give

Furthermore the historical use of wild-type alleles and mutant alleles may not necessarily hold true for all the races hence the migration to the term reference and mutant alleles.

Genetics is the study concerned with hereditary and variation. One of the most fundamental properties of all living organisms is the ability to reproduce. All organisms therefore inherit the genetic information specifying their structure and function from their parents. In the same manner, all cells arise from pre – existing cells, so the genetic material must be replicated and passed from a parent to progeny cell at each cell division. The hereditary molecules that are transmitted from one generation to the next i.e. inherited are called genes. These molecules (genes) reside in the deoxyribonucleic acid (DNA) that exist within all cells. The DNA in conjunction with a protein matrix forms nucleoprotein and become

necessarily translate into effect on drug metabolism (Henningson et al 2005).

expected to impact individualized dosing of many drugs.

**1.4 Confounding issues in pharmacogenetics** 

rise to slow acetylator status.

**2. Basic genetics** 

prior to therapy.

inhibition, induction or permanent causes such as genetic mutation, gene deletion or amplification. (Shenfield 2004).

Genetic variability is known to affect drug absorption, drug metabolism and drug interactions with receptors. These therefore form the basis for slow or rapid drug absorption, poor, efficient or ultrarapid drug metabolism and poor or efficient receptor interactions.

A genetic mutation frequency exceeding 10% of a population is considered a genetic polymorphism (Meyer 2000). Genetic polymorphism based on drug metabolizing ability is related to four phenotypic classes. The phenotype of extensive or normal drug metabolizers (EM) is characteristic of the normal population .Individuals are either homozygous or heterozygous for wild type allele. Those individuals who are heterozygous for the wild type allele may have intermediate metabolizer phenotype (IM) and may require lower than average drug dose for optimal therapeutic response. Those individuals with mutation or deletion of both alleles for the determinant of phenotypic response can be classified as poor metabolizers (PM) and therefore prone to accumulation of drug substrates in their systems with attendant effects. The fourth class, termed the ultrarapid metabolizers (UM) possess enhanced drug metabolism capabilities due to gene amplification and are prone to drug failure because drug concentrations at normal doses are expected to be too low for therapeutic effects (Meyer 2000, Davies 2006).

There are ethnical and racial differences in the frequency of variant alleles and up to 10 – 20% of patients belong to the risk groups. ( Evans 1986, Banjoko & Akinlade 2010).

#### **1.2 Mechanism of genetic polymorphism**

Pharmacogenetic polymorphism can manifest at the pharmacokinetic and pharmacodynamics levels. The pharmacokinetic level deals with gene polymorphism that modify concentrations of drugs and its metabolites at the site of their molecular action (polymorphism of drug metabolizing enzymes, drug transporters) whereas the pharmacodynamics level deal with polymorphism of action not related to its concentration (receptors, ion channels). Genetic variations are the result of multiple mechanism such as insertion, deletion, variable tandem repeats and microsatellites but the most frequent polymorphism are point mutation or single nucleotide polymorphism (SNPS). Some of the polymorphism are without consequences but others cause synthesis of altered proteins, truncated proteins, unstable proteins or proteins at the level of expression.

Genotype is the detailed gene structure of an individual whereas the more commonly measured phenotype is the outcome of metabolism of a drug in an individual. Since genotype is the result of interactions between genetic make up and the environment, it is not always concordant with phenotype.

#### **1.3 Consequences of pharmacogenetics**

The underpinning factors for the growing importance of pharmacogenetics are the necessity to prevent adverse drug reaction, obtain maximum benefits from drug therapy and reduce therapeutic failure.

inhibition, induction or permanent causes such as genetic mutation, gene deletion or

Genetic variability is known to affect drug absorption, drug metabolism and drug interactions with receptors. These therefore form the basis for slow or rapid drug absorption, poor, efficient or ultrarapid drug metabolism and poor or efficient receptor

A genetic mutation frequency exceeding 10% of a population is considered a genetic polymorphism (Meyer 2000). Genetic polymorphism based on drug metabolizing ability is related to four phenotypic classes. The phenotype of extensive or normal drug metabolizers (EM) is characteristic of the normal population .Individuals are either homozygous or heterozygous for wild type allele. Those individuals who are heterozygous for the wild type allele may have intermediate metabolizer phenotype (IM) and may require lower than average drug dose for optimal therapeutic response. Those individuals with mutation or deletion of both alleles for the determinant of phenotypic response can be classified as poor metabolizers (PM) and therefore prone to accumulation of drug substrates in their systems with attendant effects. The fourth class, termed the ultrarapid metabolizers (UM) possess enhanced drug metabolism capabilities due to gene amplification and are prone to drug failure because drug concentrations at normal doses are expected to be too low for

There are ethnical and racial differences in the frequency of variant alleles and up to 10 –

Pharmacogenetic polymorphism can manifest at the pharmacokinetic and pharmacodynamics levels. The pharmacokinetic level deals with gene polymorphism that modify concentrations of drugs and its metabolites at the site of their molecular action (polymorphism of drug metabolizing enzymes, drug transporters) whereas the pharmacodynamics level deal with polymorphism of action not related to its concentration (receptors, ion channels). Genetic variations are the result of multiple mechanism such as insertion, deletion, variable tandem repeats and microsatellites but the most frequent polymorphism are point mutation or single nucleotide polymorphism (SNPS). Some of the polymorphism are without consequences but others cause synthesis of altered proteins,

Genotype is the detailed gene structure of an individual whereas the more commonly measured phenotype is the outcome of metabolism of a drug in an individual. Since genotype is the result of interactions between genetic make up and the environment, it is not

The underpinning factors for the growing importance of pharmacogenetics are the necessity to prevent adverse drug reaction, obtain maximum benefits from drug therapy and reduce

20% of patients belong to the risk groups. ( Evans 1986, Banjoko & Akinlade 2010).

truncated proteins, unstable proteins or proteins at the level of expression.

amplification. (Shenfield 2004).

therapeutic effects (Meyer 2000, Davies 2006).

**1.2 Mechanism of genetic polymorphism** 

always concordant with phenotype.

therapeutic failure.

**1.3 Consequences of pharmacogenetics** 

interactions.

Adverse drug reactions are thought to kill many hospitalized patients worldwide. In the US alone, the estimate of deaths attributable to drug reactions is about 100,000 annually and it is believed that many of these reactions are due to genetic variations. Thus many deaths are avoidable if genetic testing or genomic information of patients are available and utilized prior to therapy.

Pharmacogenetics will therefore permit gene profiling to answer questions about drug responses and promote the design of better and safer drugs. In addition, individualized dosing has the potential of better therapeutic outcome. Therefore pharmacogenetics is expected to revolutionise drug dosing and therapy .However, there are still many challenges to overcome. These include cost implications, standardization , quality control of testing, and relevance of biomarkers and tests. Nevertheless, the advent of pharmacogenetics and establishment of guidelines by regulatory bodies like Food and Drugs Administration (FDA) European Medicines Agency (EMEA) and American Association of Clinical Chemists (AACC) are expected to impact individualized dosing of many drugs.

#### **1.4 Confounding issues in pharmacogenetics**

The understanding that drug response may be multifactoral helps us to recognize the importance of examining more than the classical "single gene-single protein concept which gave birth to pharmacogenomics. In addition, there are more evidences that modifications besides outright mutation of genes, for example, methylation of promoter region by epigenetic factor impact gene expression and drug responses. Moreover, genotype is not the only determinant of phenotype. For example, individuals whose genotypes falls extensive metabolizers via CYP2D6 can display a phenotype that would characterize them as poor metabolizers if they are co-administered low doses of quinidine which is a potent inhibitor of CYP2D6 . Therefore, differences in phenotype does not necessarily translate into difference in pharmacologic response between subjects. In the same fashion, mutation of the genes may not necessarily translate into effect on drug metabolism (Henningson et al 2005).

Because of significant racial differences in genetic composition, it is important that caution is exercised in the interpretation of genetic testing. For example different genotypes may give rise to the same phenotype.In addition, there are varieties of mutations in NAT2 that give rise to slow acetylator status.

Furthermore the historical use of wild-type alleles and mutant alleles may not necessarily hold true for all the races hence the migration to the term reference and mutant alleles.

#### **2. Basic genetics**

Genetics is the study concerned with hereditary and variation. One of the most fundamental properties of all living organisms is the ability to reproduce. All organisms therefore inherit the genetic information specifying their structure and function from their parents. In the same manner, all cells arise from pre – existing cells, so the genetic material must be replicated and passed from a parent to progeny cell at each cell division. The hereditary molecules that are transmitted from one generation to the next i.e. inherited are called genes. These molecules (genes) reside in the deoxyribonucleic acid (DNA) that exist within all cells. The DNA in conjunction with a protein matrix forms nucleoprotein and become

Pharmacogenetics: The Scientific Basis 183

**Law of segregation**: Each parent possesses 2 copies of a unit of inheritance (now called the gene) for each trait. However, only one of these two genes (an allele) is transmitted through

**Law of independent assortment**: says segregation of one gene pair occurs independently of

Chromosomes are known to be carrier of genes. Most cells of higher plants and animals are diploid. i.e. they contain two copies of each chromosome. Formation of the germ cells; the sperm and egg involves a unique type of cell division termed meiosis. In this process, only one member of each chromosome pair is transmitted to each progeny cell. Therefore, the sperm and egg are haploid containing only one copy of each chromosome. The fusion of these two haploid cells at fertilization result in a new diploid organism; the offspring which consists of one member of each chromosome pair. Behaviour of chromosome pairs is directly related to their genes indicating a strong relationship between genes and

Genetic alterations i.e. mutation which is the basis of genetic diseases was first identified in the experiment with *Drosophilia melanogaster* (the fruit fly) in the early 1900. Mutations in drosophila was observed to involve such phenotypes like eye colour and wing shape. Experimented evidences revealed that the genes governing these traits are inherited independently of each other, suggesting that these genes are located on different chromosomes that segregate independently during meiosis. Other genes are inheritable as paired characteristics and such are said to be linked to each other by virtue of being located on the same chromosome. The frequency of recombination between two linked genes depends on distance between them on the chromosomes. In addition, genes that are close to each other recombine less frequently than do genes further apart. Thus the differences with which the different genes recombine can be used to determine their relative position on the

Genes act by determining the structure of proteins which are responsible for directing cell metabolism through the activities of enzymes. Many genes encode enzymes that are important for catalysing biological synthesis (anabolic) and degradation (catabolic reactions) within a cell. These reactions grouped together into a series of reactions are called biochemical pathways and commence with the enzymes acting on their corresponding

The first indication linking genes and enzymes can be traced to 1909 when it was observed that patients suffering from phenylketonuria were suspected to have a genetic defect in the metabolism of the amino acid for phenylalanine.This line of thought was supported by the experiment of George Beadle and Edward Tatum in 1941 with the fungus; *Neurospora cassa*. Using mutant strains of the organism, they observed that each mutant required specific nutritional supplement such as a particular aminoacid for growth.Furthermore, the

By 1900, Mendel's laws of inheritance were well established and are thus stated:

a gamete to the offspring.

**2.1 Chromosomes, genes and inheritance** 

chromosome allowing the construction of a genetic map.

**2.2 Genes, proteins and enzymes** 

any other gene pair.

chromosomes.

substrate.

organized into structures called chromosomes located in the nucleus or nuclear region of cells. The genes contains coded information for the synthesis of proteins and some ribonucleic acids (RNA). Occasionally, a change may occur spontaneously in some part of the DNA. This change is called mutation and may result in an alteration of the code designated for a particular function resulting in production of a defective protein.

A mutation may lead to a change in the physical appearance of an individual or change in some other measurable attributes of the organism called a character or trait. Through the process of mutation, a gene may be changed into two or more alternative forms called alleles. Each gene occupies a specific position on the chromosomes called the gene locus. All allelic forms of a gene therefore are found at corresponding positions on genetically similar (homologous) chromosomes.

All the genes on a chromosomes are said to be linked to one another and to belong to the same linkage group. Since a gene can be changed to alternative forms by the process of mutation, a large number of alleles are theoretically possible in a population of individuals. Whenever more than two alleles are identified at a gene locus in a population, such is described as multiple allele series.

Genetic information is stored and transmitted in the four letter alphabet and language of DNA (A,C,G,T) and ultimately expressed in the twenty letter alphabet of proteins. Protein biosynthesis is called translation because it involves the biochemical translation of information between languages.

A capital letter is commonly used to designate the allele that is dominant to other alleles in the series. For example letter "R" for a character is dominant over 'r' which is an allele that is recessive to all others in the series .Intermediate in their degree of dominance between the two extremes are usually assigned the lower case letter with superscript which in this example is r\*. Many genes may contribute to a single character or trait (polygenic traits) or traits exhibiting continuous variation. In addition, each gene may have multiple phenotypic effects (pleiotropy).

Each character is controlled by a pair of genes. The progeny or offspring are therefore hybrids of the parents, inheriting a pair of gene, one each from each parent. For example for trait for tallness being represented by letter T, possible genetic composition are TT, Tt, and tt whereby T allele is dominant over t. It is expected that an offspring with tt genetic composition will be short while those with TT or Tt will be tall.

The genetic composition of a trait is referred to as the genotype and the physical appearance corresponding to the genotype, in this example tallness is called the phenotype.With different generations of offsprings i.e. the filial generations, different genotypes and corresponding phenotypes are obtainable.

The originator of the classical principles of genetics is Macgregor Mendel who made public the result of his study of peas breeding in 1865. Mendel studied the inheritance of a number of well defined traits in the pea such as seed colour and was able to deduce general rules for their transmission. He was the first to observe that each trait was determined by a pair of inherited factors later termed the genes. Mendel's findings provided the template for determination of genotypes and phenotypes of different genetic diseases of humans, animals and plants and notable examples include: sickle cell disease, albinism and thalassaemias.

organized into structures called chromosomes located in the nucleus or nuclear region of cells. The genes contains coded information for the synthesis of proteins and some ribonucleic acids (RNA). Occasionally, a change may occur spontaneously in some part of the DNA. This change is called mutation and may result in an alteration of the code

A mutation may lead to a change in the physical appearance of an individual or change in some other measurable attributes of the organism called a character or trait. Through the process of mutation, a gene may be changed into two or more alternative forms called alleles. Each gene occupies a specific position on the chromosomes called the gene locus. All allelic forms of a gene therefore are found at corresponding positions on genetically similar

All the genes on a chromosomes are said to be linked to one another and to belong to the same linkage group. Since a gene can be changed to alternative forms by the process of mutation, a large number of alleles are theoretically possible in a population of individuals. Whenever more than two alleles are identified at a gene locus in a population, such is

Genetic information is stored and transmitted in the four letter alphabet and language of DNA (A,C,G,T) and ultimately expressed in the twenty letter alphabet of proteins. Protein biosynthesis is called translation because it involves the biochemical translation of

A capital letter is commonly used to designate the allele that is dominant to other alleles in the series. For example letter "R" for a character is dominant over 'r' which is an allele that is recessive to all others in the series .Intermediate in their degree of dominance between the two extremes are usually assigned the lower case letter with superscript which in this example is r\*. Many genes may contribute to a single character or trait (polygenic traits) or traits exhibiting continuous variation. In addition, each gene may have multiple phenotypic

Each character is controlled by a pair of genes. The progeny or offspring are therefore hybrids of the parents, inheriting a pair of gene, one each from each parent. For example for trait for tallness being represented by letter T, possible genetic composition are TT, Tt, and tt whereby T allele is dominant over t. It is expected that an offspring with tt genetic

The genetic composition of a trait is referred to as the genotype and the physical appearance corresponding to the genotype, in this example tallness is called the phenotype.With different generations of offsprings i.e. the filial generations, different genotypes and

The originator of the classical principles of genetics is Macgregor Mendel who made public the result of his study of peas breeding in 1865. Mendel studied the inheritance of a number of well defined traits in the pea such as seed colour and was able to deduce general rules for their transmission. He was the first to observe that each trait was determined by a pair of inherited factors later termed the genes. Mendel's findings provided the template for determination of genotypes and phenotypes of different genetic diseases of humans, animals and plants and

composition will be short while those with TT or Tt will be tall.

notable examples include: sickle cell disease, albinism and thalassaemias.

corresponding phenotypes are obtainable.

designated for a particular function resulting in production of a defective protein.

(homologous) chromosomes.

described as multiple allele series.

information between languages.

effects (pleiotropy).

By 1900, Mendel's laws of inheritance were well established and are thus stated:

**Law of segregation**: Each parent possesses 2 copies of a unit of inheritance (now called the gene) for each trait. However, only one of these two genes (an allele) is transmitted through a gamete to the offspring.

**Law of independent assortment**: says segregation of one gene pair occurs independently of any other gene pair.

#### **2.1 Chromosomes, genes and inheritance**

Chromosomes are known to be carrier of genes. Most cells of higher plants and animals are diploid. i.e. they contain two copies of each chromosome. Formation of the germ cells; the sperm and egg involves a unique type of cell division termed meiosis. In this process, only one member of each chromosome pair is transmitted to each progeny cell. Therefore, the sperm and egg are haploid containing only one copy of each chromosome. The fusion of these two haploid cells at fertilization result in a new diploid organism; the offspring which consists of one member of each chromosome pair. Behaviour of chromosome pairs is directly related to their genes indicating a strong relationship between genes and chromosomes.

Genetic alterations i.e. mutation which is the basis of genetic diseases was first identified in the experiment with *Drosophilia melanogaster* (the fruit fly) in the early 1900. Mutations in drosophila was observed to involve such phenotypes like eye colour and wing shape. Experimented evidences revealed that the genes governing these traits are inherited independently of each other, suggesting that these genes are located on different chromosomes that segregate independently during meiosis. Other genes are inheritable as paired characteristics and such are said to be linked to each other by virtue of being located on the same chromosome. The frequency of recombination between two linked genes depends on distance between them on the chromosomes. In addition, genes that are close to each other recombine less frequently than do genes further apart. Thus the differences with which the different genes recombine can be used to determine their relative position on the chromosome allowing the construction of a genetic map.

#### **2.2 Genes, proteins and enzymes**

Genes act by determining the structure of proteins which are responsible for directing cell metabolism through the activities of enzymes. Many genes encode enzymes that are important for catalysing biological synthesis (anabolic) and degradation (catabolic reactions) within a cell. These reactions grouped together into a series of reactions are called biochemical pathways and commence with the enzymes acting on their corresponding substrate.

The first indication linking genes and enzymes can be traced to 1909 when it was observed that patients suffering from phenylketonuria were suspected to have a genetic defect in the metabolism of the amino acid for phenylalanine.This line of thought was supported by the experiment of George Beadle and Edward Tatum in 1941 with the fungus; *Neurospora cassa*. Using mutant strains of the organism, they observed that each mutant required specific nutritional supplement such as a particular aminoacid for growth.Furthermore, the

Pharmacogenetics: The Scientific Basis 185

iii. **Toxicology:** This is the study of poisonous effects of drugs and other chemicals. Although a speciality on it's own, it is nevertheless still considered under

**Stimulation:** Through direct receptor agonism and downstream effect e.g. adrenaline stimulates heart, pilocarpine stimuates salivary glands. However, excessive stimulation is often followed by depression of that function e.g. high dose of picrotoxin, a CNS stimulant,

**Depression:** Through direct receptor agonism and down stream effect e.g. barbiturates depress CNS while quinines depresses the heart. The action of this mechanism is selective.

**Stabilizing action:** In this case, the drugs seem to act neither as a stimulant nor as a depressant but to stabilize general receptor activation like buprenorphine in opioid

**Replacement:** Refers to the use of natural metabolites including hormones and vitamins in deficiency stages e.g. levodopa in Parkinsonism, insulin in diabetes mellitus, iron in anemia

**Direct beneficial chemical reaction:** As in use of antioxidants like Vitamins C,E and *B-*

**Cytotoxic action:** Selective cytotoxic action for parasite, bacterial or cancer cells, attenuating them without significantly affecting the host cells e.g. use of antibiotics like penicillin,

**Irritation:** A none selective often noxious effect applicable to less specialized cells, for example the epithelial, connective tissue cells). Mild irritation may stimulate associated function e.g. bitters increase salivary and gastric secretions which results in increased blood flow to the site. However, strong irritation may result in inflammation, corrosion, necrosis and morphological damage with resultant diminution or loss of function. Therefore caution

Metabolism of drugs and other xenobiotics involves activities that modify the chemical structure of the substances which are foreign to the body's internal mileu. These reactions often act to detoxify poisonous compounds; however in some cases, the intermediate

The purpose of biotransformation is to convert lypophilic compounds to hydrophilic ones which will facilitate their excretion. The consequences of biotransformation is changes in

should be exercised in the administration because of tendency of excessive ingestion.

**Blocking/Antagonizing action:** The drugs binds the receptor but does not activate it.

pharmacology with regards to adverse drug effects.

produces convulsions followed by coma and respiratory depression.

There are eight main drug actions and these are:

dependence or aripiprazole in schizophrenia.

carotene for free radical scavenging

zidovudin and cyclophosphamide

metabolite can themselves be toxic

pharmacokinetic characteristics.

and oestrogen replacement in women of menopausal age.

**4. Metabolism of drug and other xenobiotics** 

**3.1 Principles of drug actions** 

requirement for a specific nutritional supplement correlates with the failure of the mutant to synthesize that particular compound. Thus each mutant resulted in a deficiency in a specific metabolic pathway. Since metabolic pathways are known to be controlled by enzymes, these findings gave rise to the one – gene – one enzyme hypothesis which by implication means that each gene specified the structure of a single enzyme. However, the revelation that genes not only codes for proteins and enzymes but tRNAs resulted in this hypothesis being modified to one – gene – one – polypeptide concept.

Transfer RNA's (tRNAs) serve as adaptations between aminoacids and messenger RNA (mRNA) during translation. Prior to its use in protein synthesis, each aminoacid is attached by a specific enzyme to its appropriate tRNA. Base pairing between a recognition sequence in each tRNA and a complimentary sequence on the mRNA then directs the attached aminoacid to its correct position on the mRNA template.

#### **2.3 Genetic polymorphism**

Genetic polymorphism can be defined as differences in DNA sequence among individuals, groups or population. Genetic mutation can create genetic variance in a population and this can manifest in different ways. Somatic cell mutation can create a genetic variation in a cell population which may induce cancer and tumour when such mutation takes place in repressor genes controlling cell cycles such as p53 gene. On the other hand,germ line cell mutation can cause genetic diseases such as sickle cell disease, thalassemia, Parkinson's disease as well as defect of biochemical pathway that influence drug – receptor interaction with attendant deleterious effects on patients. Point mutation such as a single base nucleotide substitution (SNP) are common particularly with adverse drug reactions. Mutation that occurs in germ line cell would be inherited by the progeny and these mutated genes can spread in a population through the fertilization process. Mutations that occur in coding frame of DNA region that are responsible for synthesis of specific products could give rise to genetic disease. Similarly, mutation that affects enzymes responsible for biotransformation of drugs particularly C450 gene family and pharmacokinetic and pharmacodynamic gene functions can result in adverse drug reactions or drug inefficacy. These reasons make phamacogenetics an important area of study.

#### **3. Basic pharmacology**

**Pharmacology** is the study that deals with interaction of endogenously administered chemical molecules termed drugs with living systems. It involves such studies like (i) Pharmacokinetics (ii) Pharmacodynamics (iii) Toxicology


requirement for a specific nutritional supplement correlates with the failure of the mutant to synthesize that particular compound. Thus each mutant resulted in a deficiency in a specific metabolic pathway. Since metabolic pathways are known to be controlled by enzymes, these findings gave rise to the one – gene – one enzyme hypothesis which by implication means that each gene specified the structure of a single enzyme. However, the revelation that genes not only codes for proteins and enzymes but tRNAs resulted in this hypothesis being

Transfer RNA's (tRNAs) serve as adaptations between aminoacids and messenger RNA (mRNA) during translation. Prior to its use in protein synthesis, each aminoacid is attached by a specific enzyme to its appropriate tRNA. Base pairing between a recognition sequence in each tRNA and a complimentary sequence on the mRNA then directs the attached

Genetic polymorphism can be defined as differences in DNA sequence among individuals, groups or population. Genetic mutation can create genetic variance in a population and this can manifest in different ways. Somatic cell mutation can create a genetic variation in a cell population which may induce cancer and tumour when such mutation takes place in repressor genes controlling cell cycles such as p53 gene. On the other hand,germ line cell mutation can cause genetic diseases such as sickle cell disease, thalassemia, Parkinson's disease as well as defect of biochemical pathway that influence drug – receptor interaction with attendant deleterious effects on patients. Point mutation such as a single base nucleotide substitution (SNP) are common particularly with adverse drug reactions. Mutation that occurs in germ line cell would be inherited by the progeny and these mutated genes can spread in a population through the fertilization process. Mutations that occur in coding frame of DNA region that are responsible for synthesis of specific products could give rise to genetic disease. Similarly, mutation that affects enzymes responsible for biotransformation of drugs particularly C450 gene family and pharmacokinetic and pharmacodynamic gene functions can result in adverse drug reactions or drug inefficacy.

**Pharmacology** is the study that deals with interaction of endogenously administered chemical molecules termed drugs with living systems. It involves such studies like (i)

i. **Pharmacokinetic**s **:** Pharmacokinetics is the quantitative study of drug movement from administration throughout out the body till excretion. All pharmacokinetic processes involve transport of the drug across cell membrane,. absorption, distribution and

ii. **Pharmacodynamics**: Pharmacodynamics coined from two Greek words pharmacon; drugs and dynamis: power, involves the physiological and biochemical effect of drugs and their mechanism of action at organ, systemic, subcellular and macromolecular levels. The pharmacodynamic process describes all those matters concerned with the pharmacological action of a drug, whether they be determinants of the therapeutic

modified to one – gene – one – polypeptide concept.

aminoacid to its correct position on the mRNA template.

These reasons make phamacogenetics an important area of study.

Pharmacokinetics (ii) Pharmacodynamics (iii) Toxicology

**2.3 Genetic polymorphism** 

**3. Basic pharmacology** 

effect or of the toxic effect.

excretion

iii. **Toxicology:** This is the study of poisonous effects of drugs and other chemicals. Although a speciality on it's own, it is nevertheless still considered under pharmacology with regards to adverse drug effects.
