Drugs are metabolised or broken down by two sequential pathways in mammals. There are many genes involved in these pathways, all exhibiting a high degree of polymorphism (diversity at the DNA level) and have been in a number of cases associated with a number of environmentally linked diseases such as asbestosis.

The drug metabolism enzymes are broken down into two distinct families and are characterised to the type of reactions they catalyse. These are Phase I and Phase II enzymes.

Phase I Enzymes

Phase I enzymes consist of CYPp450 the well characterised family of cytochromes. Proteins belonging to this class of enzyme catalyse reactions resulting in the addition of functional groups and reactive centers e.g. SH, OH,-NH2 and -COOH groups to their xenobiotic (foreign) substrates.

There are to date at least an estimated 50 human cytochrome p450 genes and 15 associated pseudogenes, all of which share approximately 40% sequence homology due to the presence of highly conserved regions.

A number of these genes are known to be expressed and function at different levels between individuals, and are known to be one of the factors contributing to adverse drug reactions.

CYP1A1 Associated with activation of procarcinogens and polycyclic aromatic hydrocarbons. CYP1A1 is also inducible in bronchial airways and therefore metabolism by CYP1A1 should be considered when studying treatment of respiratory conditions treated by inhalers or nebulisers.

CYP1A2 High levels of variation are observed between individuals with regard to caffeine metabolism although there has been no definite link made between genotype and phenotype. CYP1A2 is also involved with the activation of dietary heterocyclic amines and aflatoxins.

CYP2C Both CYP2C9 and CYP2C19 are part of a highly conserved gene cluster located on chromosome 10.
All are expressed constitutively in the liver with allelic variation resulting in different levels of catalytic activity being observed. Individuals are designated either as poor (PM) or extensive (EM) metabolisers. The PM phenotype is recessive.

CYP2D6 The 2D6 gene cluster (usually) comprises of three genes: CYP2D6 (active), CYP2D8p and CYP2D7, both of which are non-functional. Polymorphisms within the CYP2D6 cluster are well documented and like CYP2C9 and CYP2C19, individuals are characterised as either extensive (EM) or poor (PM) metabolisers. In addition, there are also individuals carrying duplicate copies of the active CYP2D6 gene, a result of a gene amplification event. Such individuals are categorised as ultra-rapid metabolisers.

CYP3A4 The CYP3A gene cluster contains four genes including CYP3A4 located on the long arm of chromosome 7. CYP3A genes are expressed within the liver and in some individuals make up to 60% of the livers total cytochrome P450 content, and approximately 3% of total liver protein. Due to their high levels of expression with respect to other members of the cytochrome P450, variation in these genes therefore, is an important factor to consider when developing future drug treatments.

Phase II Enzymes

Enzymes involved in the Phase II or the detoxification process e.g. Glutathione - S - transferase, and the N-acetyl transferases are responsible for the inactivation of compounds prior to excretion.

Like the Cytochrome P450s, genetic variation exists within this group of enzymes with variants often exhibiting reduced activity profiles.

N-acetyl transferases

Acetylation of amine, hydroxyl and sulphurydryl groups is an important route of metabolism for a number of drugs with therapeutic importance such as Dapsone, Isoniazid and Sulphamethazine. There is significant ethnic variation in allele frequencies, for example within the NAT-1 and NAT-2 genes with up to 50% of Europeans and as little as 5% of Canadian Eskimos being classed as slow acetylators.

Glutathione-S-Transferases (GSTs)

The conjugation of glutathione to foreign compounds by GSTs is an important step in facilitating the removal of reactive oxygen intermediates from the body, thus protecting the individual from the toxic effects of many metabolites.

The GSTs, like the Cytochrome P450s, also exhibit a high degree of genetic polymorphism and in some certain cases are associated with susceptibility to a number of human diseases as well as multiple drug resistance.
mEPHX

Microsomal Expoxide Hydrolase (mEPHX) is involved in the detoxification of reactive epoxides present on polycyclic hydrocarbons. mEPHX is also involved in the metabolism of cholesterols and steroids.

As mEPHX has a wide range of substrates, and is also co-expressed with the p450 enzymes it is thought that this enzyme plays an active role

- in correcting errors in cytochrome p450/Phase I metabolism.

There are also several documented genetic variants of mEPHX confirming altered catalytic activity to the functional protein.

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