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The ultimate toxic effect of xenobiotics coming into the body is regulated by many factors, with man's ability to metabolize the chemical of key relevance. Sometimes, this metabolism activates the chemical, resulting into a more toxic metabolite whereas in other cases it ends in detoxification and excretion. Human metabolism of environmental chemicals and drugs can be influenced by way of living, nutrition and exposure elements that can induce or inhibit metabolism. Furthermore, the genetic polymorphism in humans can influence xenobiotic metabolism as it causes variability that can affect the performance of metabolizing enzymes. The impact of polymorphism has been investigated extensively for human medicines, in contrast to environmental toxicants, which are scarcely investigated. Genetic polymorphism however has been demonstrated not only to affect the disposition of therapeutic drugs and environmental toxicants. Polymorphisms can also affect detoxification by antioxidant defence genes and repair genes. By this way, genetic polymorphism may affect humans capacity to metabolize, detoxify and repair damage due to exposure to xenobiotics and thus affect susceptibility of man to xenobiotics. Nevertheless the influence of genetic polymorphism on the susceptibility of man to xenobiotic toxicity needs to be evaluated with the assistance of PBPK modeling due to the large number of non-polymorphic factors also affecting enzyme activity.
The toxic effect of xenobiotics encompasses a cascade of facts that is triggered by exposure and culminates in the manifestation of a toxic effect. Between all these steps, metabolism and the interaction with receptors are practically most crucial. The outcome of metabolism can be either detoxification or activation, the last being a more toxic product than the original chemical (Hodgson, E., Rose R.L., 2007 p.421).This dynamic equilibrium of activation and detoxification defines the final toxic effect (Rose, R.L. et al., 2005 p.156).
Xenobiotic metabolizing enzymes (XME)
Xenobiotic metabolism may depend on XME's their isoforms and their polymorphic variants. First, in phase 1 reactions, a suitable polar group is inserted into the molecule, leading to a proper substrate for phase 2 reactions. Phase 2 reactions consist of conjugation of phase 1 metabolites with endogenous compounds and result in even higher polarity and excretabilty. The results of phase 1 reactions are not always conjugated by phase 2 enzymes, because the reaction products of phase 1 XME are frequently powerful electrophiles that are able to react with nucleophilic groups on macromolecules. By this way they may be involved in activation- as well as detoxification reactions. XME often exist as different isoforms, (or isoenzymes) they are various forms of a particular enzyme that contribute to the same enzymatic process. Isoenzymes are coded for by different genes, however, that have some level of similarity. They may differ from each other by substrate selectivity, and they may be found in various organs or cells. Unlike isoenzymes, polymorphisms are permanent inherited monogenetic variations that occur in a population in minimum 2 genotypes that exist at the same gene location. If Polymorphism takes place in the nucleic acid sequence (CDS) it may affect the features of the expressed enzyme like substrate selectivity and reaction rate (kinetics).On the other hand, if polymorphism exists in the genetic regulatory network (GRN), it may affect the process of transcription/translation in a gene (table1). Polymorphism commonly determines or an individual is a poor-(PM), intermediate-(IM), extensive-(EM), or ultra-rapid metabolizer (UM) of xenobiotics, but there relevance towards environmental pollutants has not yet been investigated in detail (Hodgson, E., Rose R.L., 2007 p.421). Genetic polymorphism involved in drug metabolism results in different subgroups in the human population which have distinct drug performance properties for certain metabolic reactions (Meyer, A., Zanger, M., 1997 p.269) (table 2).
The role of genetic polymorphism in disposition of therapeutic drugs
Genetic polymorphism encompasses different structural changes in DNA. First of all nucleotides can be deleted or inserted into a gene. Duplication of nucleotides has also been reported. Copy number variation (CNV) is an alternation of the genome that results in cells bearing an abnormal number of copies or deletes of nucleotides. The second form of polymorphism is the so called repeats of short part of the DNA, or tandem repeats. Finally the Single-nucleotide polymorphism (SNP) relates to the substitution of one nucleotide by another nucleotide of the DNA.
Due to development of new technologies, it is now believed that in contrast to previous thoughts, CNV's appear more often than SNP's (Stankiewicz, P., Lupski, R.J., 2010 p.437)
Due to variation in DNA sequence within a population the most prevalent allele is defined as the 'wild-type' allele, and the minority as the 'variant' allele.
If the variant allele is present in minimal 1 % of the population by convention, this variation is regarded as polymorphism. Variations in DNA less than 1% are considered as a mutation.
The role of single nucleotide polymorphism (SNP) in genes that code for xenobiotic-metabolizing enzymes is regarded as more and more important in drugs adverse reaction (DAR) and metabolism of environmental chemicals (Ginsberg, G. et al., 2009 p.307).Today the focus is not only on drug metabolism, but it has been elaborated to the full area of drug disposition (ADME) (Evans ,W.E., Mc Leod, H.L., 2003 p.538).
Differences in drugs disposition have become increasingly important due to unforeseeable therapeutic response with both higher risk of side effects (toxicity) and low availability of the drug (sub therapeutic dose). This is basically a problem for drugs with a narrow therapeutic index (Nicolas, J.M. et al., 2009 p.408).
The cytochrome P450s are responsible for almost 75 % of phase 1 dependent drug metabolism as well as for the metabolism of an immense number of dietary components and endogenous chemicals. Furthermore from all P450 catalysed drug metabolisms, about 40 % is affected by polymorphic enzymes, resulting in ADR (Ingelman, M., 2004 p.89). Medical relevant polymorphism is observed as with CYP2C9, CYPC19 and CYP2D6 (table 3). Mutations in the CYP genes can lead to enzymes with lost, decreased, adapted or increased enzymatic performance (Ingelman, M., 2004 p.98).
Phenytoin, an antiepileptic drug, is metabolized by CYP2C9. The CYP2C9*3 variant may causes overdosing due to poor elimination of the drug. Female patients have developed neurological toxicity. This was demonstrated by measurement of serum values of the drug. The measured half-life value was five time longer than the normal half-life (Brandolese, R. et al., 2001 p.391). Even more extreme poor clearance of the drug was found in a female patient from African-American origin (table 4). Genotyping revealed that the patient was carrying the null allele CYP2Y9*6 (Johansson, I. Sundberg, I., 2010 p.9).
A marked example of the influence of polymorphism is treatment with the drug clopidogrel, which is one of the most sold drugs (antiplatelet aggregation). Due to defective (in PMs) and rapid type (in EMs) CYP2C19 alleles. Thrombosis (low active metabolite levels), and bleeding (enhanced response) can appear respectively (Johansson, I., Ingelman, M., 2010 p.10-11).
Genetic polymorphism of CYP2D6 affects the kinetics of 50 % of all drugs. This can result in besides toxicity and low drug response, also in variable efficacy of the therapy. (Ingelman, M., 2005 p.6). Mainly poor metabolizers (prevalent in Caucasian) and ultra-rapid (prevalent in Ethiopians) have important clinical effects (Teh, L.K., Bertilsson, L., 2012 p.62).
Genetic polymorphism in antioxidants defence genes and their significance in ROS levels
Variations in antioxidant enzymes have been speculated for some years to be potential threats for the genetic susceptibility to malignant neoplasms. MnSOD, as the starting element in the route of detoxification of mitochondrial ROS, has been discussed since a long time in the contexts of vulnerability of malignant cells.
MnSOD catalyzes the dismutation of reactive oxygen species. For that reason it is most likely that polymorphism of MnSOD gene are of high significance in the regulation of ROS levels in the cell. Low- and high expression of MnSOD have been linked to cancer formation and inhibition of cancer growth respectively (Bag, A., Bag, N., 2008 p.3299).
Still, additional studies are required to gain knowledge on the connection between MnSOD polymorphism and cancer risk (Bag, A. ,Bag, N., 2008 p.3305).
The role of CYP2B6 in human metabolism of environmental chemicals
Genetic polymorphism has been discovered by searching for an explanation for unexpected responses to medication. Later gene-environmental interactions have been linked with several studies that were describing susceptibility to cancer and other adverse health effects (Ginsberg, G. et al., 2010 p.577). Chlorpyrifios (an insecticide) is metabolized (by P-450enzymes) to the corresponding active metabolite CPF-oxon (fig 1). Genetic polymorphism of PON1 detoxification has been shown to result in variable hydrolysis of CPF-oxon to 3,5,6-trichloro-2-pyridinol (TCP) and diethyl phosphate (fig 1). Therefore susceptibility to chlorpyrifos may occur due to variations in the extent of metabolic detoxification of the toxic CPF-oxon (Timchalk, C. et al., 2002 p.52).
Genetic polymorphism in repair enzymes
Albeit metabolism genes have been described to play a key role, there is an increasing knowledge that repair genes may also undergo genetic polymorphism. Three major base excision repair (BER) genes, diphosphate ribosyl transferase (ADPRT), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum complementary group D (XPD), may have sequence variants that can modulate DNA repair capacity. By this way, the susceptibility of different disorders is affected by means of specific alleles of polymorphic genes. Thus, variations in these genes influence DNA repair capacity in normal population, and may be linked to differences in cancer risk (jiang, J et al., 2009 p.306).
Age variation in enzyme capacity
Therapeutic effects of medication in adolescents, infants, and newborns also vary. Adults and adolescents have a more developed liver compared to neonates, as a result, enzymes levels in neonates such as CYP450 (CYP)2D6 are below normal adult levels. So far no polymorphism is involved.
However, when UM breastfeeding mother take codeine for post-child birth pain (CYP2D6 gene), they give rise to an overdose of morphine in their baby. Enhanced O-demethylation of codeine to morphine in the mother is due to an additional copy of the CYP2D6 gene (Avard, D. Joly, Y., 2008 p.275).
Role of PBKP models in evaluation of polymorphism
PBKP modeling is a mathematical modeling technique for prediction of ADME of chemicals in humans or animals. It is particularly used for pharmaceutical research & development and for hazard & risk assessment of chemicals in general. Polymorphic metabolizing enzyme systems are potentially important sources of pharmacokinetic variability. Besides polymorphism based changes in enzyme function, various internal and external factors may also determine which particular pathway will be used in metabolism. Therefore demonstration of variability in a particular enzyme system in isolating from naturally occurring conditions is complex. Therefore a more elaborated approach, involving PBKP modeling, is recommended (Ginsberg, G. et al., 2009 p.275).
The term 'xenobiotic' encompasses a broad spectrum of substances that are not normally expected to be present in the body. Many of these chemicals, including industrial chemicals, environmental pollutants and especially drugs, serve as substrates for enzymatic metabolism. It is clear that genetic variation is an intrinsic feature of all living organisms (Poulsen, EH. Loft, S., 1994 p. 211). Genetic polymorphism of xenobiotic metabolizing enzymes can have extreme influence on enzyme activity, with significant impact on xenobiotic fate. This may lead to interindividual variability in efficacy/toxicity of drugs and disease susceptibility.
In contrast to drugs, today the implications of genetic polymorphism on toxicity and risk assessment of environmental toxicants have been obtained little attention.
Nevertheless different factors can compensate the effect of a polymorphism, comprising enzymes with overlapping function (isoenzymes), and other physiological factors (e.g., blood flow limitation). As a consequence, the significance of the emphasized polymorphisms must be investigated by physiologically based pharmacokinetic (PBKP) models (Ginsberg, G. et al., 2010 p.610).
It has been calculated that adverse drug reactions leading to more than 100.000 deaths every year in America (Ingelman, M., 2003 p.89).
Today it is known that most xenobiotic-metabolizing P450s are polymorphic, and allelic variants have been listed and identified (Johansson, I. Ingelman, M., 2010 p.2). The clinical effect of genetic polymorphism of drug metabolism enzymes is higher in drugs with a small therapeutic window, and where only one metabolic pathway is involved for more than 90 %. Today, it is desirable that new drugs are eliminated by means of more than one metabolic pathway (Teh, L.K. Bertilsson, L., 2012 p.62). Moreover, for some drugs, pharmacokinetic information can now be obtained from the product labels (McGraw, J. Waller, D., 2012 p.371).
Appendix: Tables and figures
Table 1: Genetic polymorphism enzyme variability (Ginsberg, G. et al., 2009 p.307-308)
Type of enzyme modification
Type of effect
Reading frame (RNA)
Amount of enzyme
Inducibility of enzyme
Single nucleotide (SNP)
Change in catalytic activity(Loss,deletion )
Change in selectivity to substratre
Table 2: Calculated dose adjustment due to genetic polymorphism in CYP2D6 for three antidepressants at different locations (Ingelman, M., 2005 p.11) (Teh, L.K., Bertilsson, L., 2012 p.62).
Ethiopians & Saudi Arabians
Imipramine in mg/day
Maprotiline in mg/day
Nortriptyline in mg/day
Table 3: Important polymorphism for drugs in human P450s metabolism
of variant alleles
Table4: Reduced Elimination of phenytoin due to genetic polymorphism (Johansson, I. Sundberg, I., 2010 p.9)
Half-life in hours
Figure 1: Chlorpyrifos metabolic activation and detoxification