Altered Drug Response Research Articles

Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2

Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B(1)), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme inducibility whereas *1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.

Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.

Personalized pharmacotherapy for Type 2 diabetes mellitus.

Genome-wide linkage and association studies have been applied to Type 2 diabetes in order to discover common genetic variation that contributes to disease risk. While there has been progress in understanding how genetic variation predisposes to diabetes, there is less of an understanding of how genetics can alter drug response. The hope is that in the future, pharmacogenetics can help guide the treatment of diabetes, thereby improving control while minimizing side effects in a large group of patients.

Hybrids of aneuploid human cancer cells permit complementation of simple and complex cancer defects

Causes for the complex phenotypes of cancers, such as altered differentiation, invasion, and metastasis, are not known, and multigenic defects are likely. In contrast, well-defined deficiencies, such as those affecting DNA-repair mechanisms and enzymatic path¬ways, are simple, typically caused by one or a few gene mutations. Complemen¬tation by introducing defined genetic elements is used to study simple cancer phenotypes, while complementation by the fusion of whole cells is employed occasionally for complex ones. Hybrids formed solely from the common lines (aneuploid due to chromosomal instability, CIN) are rarely reported. We created stable hybrids of two CIN lines, producing a nearly complete genetic sum of the parental karyotypes. Complementation of a simple cancer phenotype, a Fanconi anemia pathway defective in both parental lines, occurred in all hybrids, restoring the normal drug-resistance phenotype. The grossly defective mitotic spindle checkpoint present in both parental lines was partially corrected in some hybrids, supporting a multigenic origin rather than a single gene defect. Using Affymetrix 100K SNP chips, we mapped chromosomal loci differing among the phenotypically distinct hybrid clones. Fusing CIN cell lines to form mapped hybrids offers new tools for positional cloning or classification of simple and complex cancer phenotypes, including mechanical defects and altered drug responses.

A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450

Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease and altered drug response. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment, and conducting individualized pharmacotherapy. Numerous nsSNPs have been found in genes coding for human cytochromes P450 (P450s), but there is poor knowledge on the relationship between the genotype and phenotype of nsSNPs in P450s. We have identified 791 validated nsSNPs in 57 validated human CYP genes from the National Center for Biotechnology Information Database of Single Nucleotide Polymorphism and Swiss-Prot database. Using the polymorphism phenotyping (PolyPhen; http://genetics.bwh.harvard.edu/pph) and sorting intolerant from tolerant (SIFT; http://blocks.fhcrc.org/sift/SIFT.html) algorithms, 39 to 43% of nsSNPs in CYP genes were predicted to have functional impacts on protein function. There was a significant concordance between the predicted results using the SIFT and PolyPhen algorithms. A prediction accuracy analysis found that approximately 70% of nsSNPs were predicted correctly as damaging. Of nsSNPs predicted as deleterious, the prediction scores by the SIFT and PolyPhen algorithms were significantly associated with the numbers of nsSNPs with known phenotype confirmed by benchmarking studies, including site-directed mutagenesis analysis and clinical association studies. These amino acid substitutions are supposed to be the pathogenetic basis for the alteration of P450 enzyme activity and the association with disease susceptivity. This prediction analysis of nsSNPs in human CYP genes would be useful for further genotype-phenotype studies on individual differences in drug clearance and clinical response.

Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition

1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1.2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes.3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs.4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood–brain barrier.5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins.6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases.7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug–drug interactions with altered drug pharmacokinetics and response.8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1.

Pharmacogenetics: potential role in the treatment of diabetes and obesity

Background: Common genetic variation is associated with increased risk of common metabolic diseases such as type 1 and type 2 diabetes, and obesity. Increasing experience with genetic association studies has led to an understanding of the large sample sizes required to detect a weak to moderate genetic predisposition to disease, the need to reproduce such associations in independent cohorts, and the statistical criteria required to detect a true association. This approach has been used successfully to identify disease-associated gene variation usually in representative populations of large numbers. Objective: To review the current understanding of how common genetic variation influences predisposition to, and treatment of, metabolic disease. Methodology: Review of scientific literature. Results: While there has been progress in understanding how genetic variation predisposes to diabetes and obesity, and how candidate genes may alter drug response, several caveats limit the interpretation and significance of pharmacogenetic studies published to date: those caveats typically include relatively small numbers of participants and choice of endpoints in determining gene-associated differences in response, which may not be clinically significant or relevant as a biomarker or predictor of a desired clinical effect. The genetic variants studied at a given locus are often limited in number and may not represent a comprehensive map of the region under study. Conclusions: The pharmacogenetic associations in diabetes and obesity that have been reported to date have had limited impact on the choice of individual treatments. We perceive, however, that this field is in its infancy in these multifactorial metabolic diseases, and with further advances and future drug intervention trials designed in a way that allows a more clear interpretation of the impact of genetic variation on differences in drug response in obesity and diabetes, it is anticipated that pharmacogenetics will have a significant impact on individualizing medical care.

Toward colloid-based biosensors for SNP genotyping and personalised medicine applications

Therapeutic drugs can assist some patients, however, other individuals may exhibit no response. Furthermore, a drug that is normally considered to be safe can have toxic effects in a small proportion of the population, occasionally causing death. Many altered drug responses depend on the genetic constitution of the recipient. The analysis of specific DNA markers within the genome of an individual [single nucleotide polymorphism (SNP) genotyping] could potentially identify subjects at risk in clinical trials and may enable clinicians to individualise medical therapy. The development of technology for personalised medicine relies on the ability to accurately and rapidly identify SNPs in genetic material. Some of the biotechnology tools for SNP identification are colloid-based biosensors, which are proving to possess several advantages over the traditional microarray format. Here, we survey the current technologies used for SNP genotyping and review colloid-based biosensors which are emerging as a higher throughput, potentially more accurate, technology.

The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor

Mutations in the GLRA1 gene, which encodes the alpha1-subunit of the inhibitory glycine receptor (GlyR), are the underlying causes in the majority of cases of hereditary startle disease (OMIM no. 149400). GlyRs are modulated by alcohols and volatile anesthetics, where a specific amino acid at position 267 has been implicated in receptor modulation. We describe a hyperekplexia family carrying the novel dominant missense allele GLRA1(S267N), that affects agonist responses and ethanol modulation of the mutant receptor. This study implies that a disease-related receptor allele carries the potential to alter drug responses in affected patients.

The BH3-Mimetic Obatoclax Restores the Response to Dexamethasone in Glucocorticoid-Resistant ALL through Induction of Autophagy.

Incorporation of cell death-inducing agents into current therapeutic regimens is an attractive strategy to improve treatment for drug resistant leukemia. We tested the potential of the pan-Bcl-2 family antagonist BH3 mimetic obatoclax (GX15-070) to restore the glucocorticoid (GC) response in GC-resistant childhood acute lymphoblastic leukemia (ALL). One tenth of the IC50 dose of obatoclax was sufficient to restore GC-sensitivity in vitro of primary ALL cells from T-cell and precursor B-cell ALL patients with poor in vivo response to prednisone. In GC-resistant cell lines, this effect was associated with strong caspase activation, externalization of annexin V and resulted in caspase-dependent cell death. Overexpression of either Mcl-1 or Bcl-XL interfered with the cytotoxic effect of obatoclax as single agent, but not with the GC-sensitizing effect of low-dose obatoclax. We hypothesized that an alternative mechanism could be involved, which may be independent of the regulation of the intrinsic pathway of apoptosis by members of the Bcl-2 family. Consistent with this hypothesis, we observed that obatoclax was also cytotoxic for mouse embryonal fibroblasts with homozygous deletions of Bax and Bak (Bax/Bak DKO), in which the intrinsic pathway is blocked completely. The IC50 of obatoclax on DKO cells was 200 nM. Given that induction of autophagy can lead to an alternative mode of programmed cell death, and because autophagy induction is also controlled by anti-apoptotic Bcl2-family members via an interaction with the essential autophagy BH3-only protein Beclin-1, we asked whether autophagy involved in mediating the therapeutic effects of obatoclax in our model. Using the LC3-GFP reporter system, we detected strong induction of autophagic vacuoles after treatment of Bax/Bak DKO and ALL cells with IC50 concentrations of 200 and 800 nM obatoclax, respectively. Autophagy induction was confirmed by detection of the expected cleavage products of the endogenous autophagy protein LC-3 by Western blotting. Low dose obatoclax induced autophagy only in combination with dexamethasone. Inhibition of autophagy using 3-methyl-adenosine (3-MA) or downregulation of Beclin-1 by RNA interference abrogated the GC-sensitizing effect of obatoclax completely in ALL cells, and strongly interfered with the cytotoxic effect of obatoclax on DKO cells. The restoration of GC-resistance by Beclin-1 knock-down was associated with a marked decrease of caspase-3 activation. These data indicate that induction of autophagy by obatoclax is required to initiate a caspase-dependent death pathway. Furthermore, low-dose obatoclax did not impair the response to daunorubicine, vincristine and asparaginase in GC-resistant ALL cells, suggesting that induction of autophagy will not lead to drug resistance in this context. Ongoing experiments will validate the effect of obatoclax in a leukemia xenograft model of GC-resistant ALL. Collectively, our results support the notion that the incorporation of obatoclax into GC-based regimens is a promising strategy to improve the treatment of GC-resistant ALL and provide new angles for the investigation of mechanisms that are implicated in altered drug responses in resistant disease.

Naphthoindole-based analogues of tryptophan and tryptamine: Synthesis and cytotoxic properties

The efficacy of anthracycline based anticancer drugs is limited by pleiotropic drug resistance of tumor cells. Aiming at the design of anthracyclinone congeners capable of circumventing drug resistance, we synthesized naphthoindole containing derivatives of tryptophan and tryptamine. In doing so we adapted the traditional, gramine based approach for tryptophan and tryptamine synthesis. The most potent new compound, 3-(2-aminoethyl)-4,11-dihydroxynaphtho[2,3- f]indole-5,10-dione ( 16), was equally cytotoxic (IC 50 within low micromolar concentrations) for human K562 leukemia and HCT116 colon carcinoma cell lines and their isogenic sublines with genetically defined determinants of altered drug response, that is, the expression of the multidrug transporter P-glycoprotein and loss of pro-apoptotic p53. Each of these mechanisms conferred resistance to the reference drug adriamycin. In contrast, naphthotryptamine 16, although less potent than adriamycin, was equally toxic for wild type cell lines and drug resistant counterparts. Moreover, at 3–5 μM 16 inhibited topoisomerase I in vitro. Thus, our novel naphthoindole based derivative of tryptamine gained new activities important for anticancer therapy, namely, suppression of topoisomerase I and the ability to overcome resistance mediated by P-glycoprotein expression and p53 dysfunction.

Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine

BackgroundThe mouse C57BL/6 (C57) and DBA/2J (DBA) inbred strains differ substantially in many aspects of their response to drugs of abuse. The development of microarray analyses represents a genome-wide method for measuring differences across strains, focusing on expression differences. In the current study, we carried out microarray analysis in C57 and DBA mice in the nucleus accumbens of drug-naïve and morphine-treated animals.ResultsWe identified mRNAs with altered expression between the two strains. We validated the mRNA expression changes of several such mRNAs, including Gnb1, which has been observed to be regulated by several drugs of abuse. In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt). Data mining of expression and behavioral data indicates that both Gnb1 and Comt expression correlate with aspects of drug response in C57/DBA recombinant inbred strains. Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences. These analyses identified axon guidance genes, particularly the semaphorins, as showing altered expression in the presence of morphine, and plasticity genes as showing altered expression across strains. Pathway analysis of genes showing strain by treatment interaction suggest that the phosphatidylinositol signaling pathway may represent an important difference between the strains as related to morphine exposure.ConclusionmRNAs with differing expression between the two strains could potentially contribute to strain-specific responses to drugs of abuse. One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse. Similarly, a role for Gnb1 in responses to multiple drugs of abuse is supported by expression data from our study and from other studies. Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains.

Drug-drug Interactions and Statin Therapy

Drug-drug interactions (DDIs) among widely and chronically prescribed medications are a relevant health issue in clinical practice. Reported incidences in outpatients range from 9.2% to 70.3% for drug interactions of any severity and from 1.2% to 23.3% for those considered of major relevance. Due to the progressive population ageing in Western Countries, concern has been raised about risks of clinically relevant DDI, as a result of polytherapy. Indeed, elderly patients may have multiple disease states and, therefore, may require a variety of different drugs. According to a recent study, the elderly population uses on average 7.0 drugs per person. In addition to polypharmacy, other factors such as age-related physiologic changes, concomitant diseases, genetic constitution and diet may alter drug response, thus predisposing patients to adverse effects and drug interactions. Drug–drug interactions may lead to adverse drug reactions that can be severe enough to require hospitalization, with the proportion of hospital admissions due to DDIs ranging from 0% to 3.8%. However, combinations of potentially interacting drugs do not necessarily result in adverse clinical manifestations, if they are knowingly prescribed and properly managed. Pharmacokinetic drug interactions in particular are often manageable, and their risk may be lessened by dose adjustment. Otherwise, the burden of drug-drug interaction, in terms of patient’s safety, may be reduced by preventing concomitant use of potentially interacting drugs and, whenever possible, by replacing drugs at interaction risk with effective but safer alternative medications belonging to the same drug class. It is the case of statins that undergoes different metabolism via cytochrome P-450 (CYP) superfamily: lovastatin, simvastatin and atorvastatin are mostly metabolized by CYP3A isoenzymes, fluvastatin by CYP2C9, while pravastatin and rosuvastatin are not significantly metabolized by this system. Although statins are the most widely used lipid lowering agents, physicians seem to be not adequately aware about their pharmacokinetic properties, and, consequently, about their interaction risk. Indeed, coprescribing of statins with potentially interacting medications, despite availability of therapeutic alternatives, has been previously reported in general practice. In this issue of the Southern Medical Journal, authors describe a case report of drug-drug interaction in a 61-year-old patient who was chronically treated with atorvastatin (plus ezetimibe and niacin) and antiseizure drugs, phenobarbital and phenytoin. Interestingly, lipid lowering therapy was successful only after phenytoin discontinuation. This paper supports the key role of CYP3A4 isoenzyme in pharmacokinetic interactions of statins. In this circumstance, phenytoin, as CYP3A4 inducer, may have reduced atorvastatin effectiveness by increasing its metabolism. In addition, this case report highlights that concomitant prescription of statins and other drugs at interaction risk may lead not only to potentially severe DDIs, but to lipid lowering ineffectiveness as well. In conclusion, inhibitors, as well as inducers of CYP3A4 isoenzyme, might be the cause of potential drug interactions with statins, as suggested by this case report. Clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided. On the other hand, health national systems should implement prevention strategies targeted to increase the awareness of health professionals about the interaction risks of widely prescribed drugs, like statins, and, finally, to improve the management of polytherapy.

Drug-Herb Interactions: Eliminating Toxicity with Hard Drug Design

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called "hard drugs" that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.

Mouse embryonic fibroblast cells from transgenic mice overexpressing tNOX exhibit an altered growth and drug response phenotype

Mouse embryonic fibroblast (MEF) cells prepared from transgenic mice overexpressing a cancer-specific and growth-related cell surface NADH oxidase with protein disulfide-thiol interchange activity grew at rates approximately twice those of wild-type embryonic fibroblast cells. Growth of transgenic MEF cells overexpressing tNOX was inhibited by low concentrations of the green tea catechin (-)-epigallocatechin-3-gallate (EGCg) or the synthetic isoflavene phenoxodiol. Both are putative tNOX-targeted inhibitors with anti-cancer activity. With both EGCg and phenoxodiol, growth inhibition was followed after about 48 h by apoptosis. Growth of wild-type mouse fibroblast cells from the same strain was unaffected by EGCg and phenoxodiol and neither compound induced apoptosis even at concentrations 100-1,000-fold higher than those that resulted in apoptotic death in the transgenic MEF cells. The findings validate earlier reports of evidence for tNOX presence as contributing to unregulated growth of cancer cells as well as the previous identification of the tNOX protein as the molecular target for the anti-cancer activities attributed to both EGCg and phenoxodiol. The expression of tNOX emerges as both necessary and sufficient to account for the cancer cell-specific growth inhibitions by both EGCg and phenoxodiol.

Heart Transplantation and Altered Drug Response, Part II: Pharmacologic Management of Post‐Transplantation Complications

Heart Transplantation and Altered Drug Response, Part II: Pharmacologic Management of Post‐Transplantation Complications

Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum

The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo-4 phenotype to those Pgh-1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh-1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed.

Synthesis and structure–activity relationship studies of 4,11-diaminonaphtho[2,3- f]indole-5,10-diones

We describe the synthesis of derivatives of 4,11-diaminonaphtho[2,3- f]indole-5,10-dione and their cytotoxicity for human tumor cells that express major determinants of altered anticancer drug response, the efflux pump P-glycoprotein, and non-functional p53. Nucleophilic substitution of methoxy groups in 4,11-dimethoxynaphtho[2,3- f]indole-5,10-dione with various ethylenediamines yielded the derivatives of 4,11-diaminonaphtho[2,3- f]indole-5,10-dione, the indole containing analogues of the antitumor agent ametantrone. The cytotoxicity of novel compounds for multidrug resistant, P-glycoprotein-expressing tumor cells is highly dependent on the N-substituent at the terminal amino group of the ethylenediamine moiety. Whereas p53 null colon carcinoma cells were less sensitive to the reference drug doxorubicin than their counterparts with wild type p53, the majority of novel naphthoindole derivatives were equally potent for both cell lines, regardless of the p53 status.

Heart Transplantation and Altered Drug Response, Part I: Heart Transplantation and Innervation

This first in a two‐part series of articles will review heart transplantation and the changes in innervation that occur as a result of the surgical procedure. The second article will review how individual drug response is altered and will outline management guidelines for treatment of specific conditions.

The role of drug-metabolising enzymes in clinical responses to chemotherapy

Interindividual differences in efficacy and toxicity of cancer chemotherapy are especially important given the narrow therapeutic index of these drugs. Pharmacokinetic and pharmacodynamic responses to chemotherapy are difficult to predict in a particular patient as numerous variables (e.g., age, gender, concomitant medications and concomitant illness) can alter drug responses. Inherited variations in genes involved in drug metabolism have also been shown to contribute to altered responses to cancer treatment. There are several clinically relevant examples of genetic polymorphisms in drug-metabolising enzymes that alter outcomes of patients treated with chemotherapy agents. It may be possible to predict a patients response to a particular chemotherapy agent based on knowledge of their genetic composition through invivo phenotyping of drug-metabolising enzymes.