Current Pharmacogenomics, Vol. 2, No. 2, 2004
Contents
Pharmacogenetics
and Anaesthesiology Pp. 119-135
Thierry Girard and
Christoph H. Kindler
Thymidylate
Synthase Gene in Pharmacogenetics Pp. 137-147
Kazuyuki Kawakami
Impact of HLA
Haplotype on the Response to Antipsychotic Treatment of Schizophrenia Pp.
149-155
L. Lahdelma and S. Koskimies
Interaction
Between Genetic Polymorphisms in Renin-Angiotensin System (RAS) and Therapeutic
Efficacy of RAS Blockade in IgA Nephropathy Pp. 157-162
I. Narita and F. Gejyo
Old Drugs-Current
Perspectives Pp. 163-173
S.A. Coulthard and L.A. Hogarth
Genomic Strategies
in Transplantation “The Right Drug for the Right Patient” Pp. 175-184
Bernd Schroppel
Molecular
Mechanisms Underlying Behavioral Effects of Cocaine: Lessons From Knockout Mice
Pp. 185-202
F. Scott Hall, Ichiro Sora and George R. Uhl
Phenotyping and
Genotyping of the Ryanodine Receptor-Associated Genetic Diseases Using
Peripheral Lymphocytes Pp. 203-208
Yoshitatsu Sei and Sheila M. Muldoon
The Role of
Cytochrome P450 in Herb-Drug Interactions Pp. 209-218
Abstracts
[Back
to top] Pharmacogenetics and Anaesthesiology
Thierry Girard and Christoph H. Kindler
Pharmacogenetics was initiated in the 1950s by the observation of prolonged postoperative apnoea due to aninherited reduction in metabolism of the neuromuscular blocking agent succinylcholine. The enzymebutyrylcholinesterase is responsible for the hydrolysis of succinylcholine. Besides the normal (usual, U) variant, there areatypical (A), silent (S), fluoride-resistant (F), and J, K, and H variants of butyrylcholinesterase with decreased hydrolyticactivity or reduced plasma concentration. Malignant hyperthermia is a potentially fatal anaesthetic disorder whoseinherited nature was recognised in 1960. Linkage analyses have located the primary genetic site of malignanthyperthermia in the gene encoding for the skeletal muscle type ryanodine receptor and today over 30 mutations have beenidentified in this gene. The standard diagnostic procedure to test for malignant hyperthermia susceptibility is the invasivein vitro muscle contracture test. However, present and future research focuses on molecular genetic investigations forselected individuals. Of additional importance to the anaesthesiologist are the genetic influences on the pharmacology ofopioids, benzodiazepines, adrenergic drugs, volatile anaesthetics, and responses to pain. Recent data also suggest anassociation between specific genotypes and the risk of adverse peri-operative clinical outcomes. Identification of suchgenotypes may not only provide insight into the variable responses of patients to anaesthetic drugs, but it also mightpotentially decrease anaesthetic morbidity and mortality through pre-operative risk assessment and administration ofprophylactic therapy.
[Back
to top] Thymidylate Synthase Gene in
Pharmacogenetics
Kazuyuki Kawakami
Thymidylate synthase (TS) is the target for widely used anticancer agent 5-fluorouracil (5-FU) and a number ofother TS inhibitors are now either in clinical use or under development. The TS gene has a variable number of tandemrepeat (VNTR) sequence, mainly 2 repeats (2R) and 3 repeats (3R), which are promising candidates for prediction of theeffectiveness and adverse drug reactions of TS inhibitors. It has been demonstrated both in vitro and in vivo that the 3Rallele is associated with higher levels of expression of TS mRNA or TS protein as compared to the 2R allele. Thisassociation provides a plausible explanation for the clinical observations that homozygous 3R/3R patients have a lowerprobability of response and less frequent adverse drug effects of 5-FU-based chemotherapy than those homozygous for2R/2R or heterozygous for 2R/3R. However, some studies found neither an association between TS VNTR genotype andTS expression nor any relationship between the genotype and clinical outcome of 5-FU-based chemotherapy. Recentstudies suggested that other polymorphisms, gene alterations of TS and cancer phenotypes relevant to TS VNTRpolymorphism may be involved in the outcome of 5-FU-based chemotherapy. These variables include loss ofheterozygosity at the TS locus, novel single nucleotide polymorphism of TS, TS 1494del6 polymorphism andmethylenetetrahydrofolate reductase polymorphism. Future clinical trials should collect information regarding thesegenetic variables to evaluate their predictive value and realize tailored chemotherapy in 5-FU-based chemotherapy.
[Back to top] Impact of HLA Haplotype on the Response to
Antipsychotic Treatment of Schizophrenia
L. Lahdelma and S. Koskimies
The response to antipsychotic drugs could be one attempt to develop a candidate phenotype of schizophreniaand deconstruct the illness for genetic analysis. This review discusses six studies on the association between HLA and theresponse to antipsychotic drugs. Three studies implicate an association between class I antigens. However, there areconsiderable limitations due to the small sample size, the different genetic backgrounds of the study subjects, varyingdiagnostic criteria, lack of standard criteria for drug response or refractoriness, inappropriate statistical methodology andvarying HLA typing methods. Only for HLA-A1 was an association with response to standard neuroleptic treatment foundrepeatedly, indicating that the presence of HLA-A1 could predict a poorer outcome with conventional neuroleptictreatment. An association between HLA specificity and antipsychotic drug response may represent linkage disequilibriumwith genes predisposing to schizophrenia on chromosome 6. Further studies are warranted with larger sample sizes inethnically homogeneous populations, and standard criteria should be used for characterising the subjects.
[Back to
top] Interaction Between Genetic Polymorphisms in Renin-Angiotensin
System (RAS) and Therapeutic Efficacy of RAS Blockade in IgA Nephropathy
I. Narita and F. Gejyo
Blockade of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme inhibitor and/orangiotensin receptor blocker, has been well appreciated as a renoprotective treatment in proteinuric glomerular diseases.However, not all patients with glomerular diseases respond well to this therapy. It would be important to predict therenoprotective effects of anti-hypertensive agents for individual patients with renal disease. The inter-individual variationin responsiveness to RAS blockade has been suggested to be in part genetically determined, whereas the results ofprevious reports, which mainly tested the interaction between the efficacy of angiotensin-converting enzyme (ACE)inhibitors and ACE insertion/deletion (I/D) polymorphism, have been conflicting in both diabetic and non-diabetic renaldiseases. Some of the recent progress in human genome science can be applied to these problems. In particular, singlenucleotide polymorphism of A2350G, an ACE gene variation other than the I/D polymorphism, which has a strongerassociation with the circulating level of ACE, has been shown to be a candidate marker for responsiveness to RASblockade. In addition, angiotensinogen gene polymorphisms may also be involved in the inter-individual difference in theresponsiveness to the renoprotective efficacy of the RAS blockade.
This review focuses on the interface between genomics and therapeutics in the renin-angiotensin system in IgAN, which is the most prevalent form of primary glomerulonephritis and one of the major causes of end-stage renal disease in the world.
[Back
to top] Old Drugs-Current Perspectives
S.A. Coulthard and L.A. Hogarth
The thiopurine drugs, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are usedin the treatment of acute leukaemias. A derivative of 6-MP, azathioprine, and 6-MP itself areused as immunosuppressants, in the treatment of inflammatory bowel disease, autoimmuneconditions and following transplantation.
The thiopurines are pro-drugs and need to be metabolised to exert their cytotoxic effects. Oneprominent cytotoxic action of these drugs is their incorporation into DNA and RNA afterconversion to thioguanine nucleotides (TGNs). Competing with TGN formation is methylation of the pro-drugs and theirmetabolites by thiopurine methyltransferase (TPMT). This enzyme exhibits wide inter-individual variation in activity,which appears to be due, at least partly, to the presence of single nucleotide polymorphisms (SNPs).
Variation in TPMT activity has an effect on the metabolism and cytotoxicity of the thiopurine drugs. Levels of TGNproduction, during treatment with the thiopurine drugs, have been shown to be inversely related to TPMT activity. LowTPMT activity has been associated with profound and life-threatening myelosuppression, whereas high TPMT levels havebeen associated with decreased efficacy in treatment with 6-MP or azathioprine. There is also a possible relationshipbetween TPMT activity and the development of secondary malignancies.
This article will review the effect of known SNPs on TPMT activity and consequences for thiopurine drug metabolism and cytotoxicity. The case for pre-treatment screening for TPMT status will also be addressed.
[Back
to top] Genomic Strategies in Transplantation “The Right
Drug for the Right Patient”
Bernd Schroppel
Purpose of review: The purpose of this review is to summarize recent advances in the area of genetic polymorphisms in genes affecting immunosuppressive drug bioavailability with a specific emphasis on solid organ transplantation.
Recent findings: Due to recent advances in molecular techniques, there has been an abundance of publications describing genetic variability in molecules relevant to pharmacogenetics. The initial studies in the field of transplantation demonstrate some associations between polymorphisms in these candidate genes with outcomes in organ transplantation.
[Back
to top] Molecular Mechanisms Underlying Behavioral Effects of Cocaine:
Lessons From Knockout Mice
F. Scott Hall, Ichiro Sora and George R. Uhl
Transgenic and gene knockout techniques are now important methods for the research of the molecular basesof drug action. This review examines the effect of gene knockouts on the behavioral consequences of cocaineadministration, especially cocaine locomotor activation and rewarding/reinforcing actions. These studies documentinteracting effects of products of several genes in providing the primary sites for cocaine reward. They highlight theinfluences of different gene products expressed in different brain circuits on cocaine reward and cocaine-stimulatedlocomotion. These influences do not produce equivalent consequences for all behavioral effects of cocaine, allowinggenetic dissociation of the mechanisms of the different sequelae of cocaine administration. The data also point tosubstantial compensatory changes in the brains of single- and multiple- gene knockout mice. Studies of geneknockouts from several neurotransmitter and cellular regulatory systems support a broad based approach to thinkingabout cocaine actions that supplements traditional neuropharmacological approaches.
[Back
to top] Phenotyping and Genotyping of the Ryanodine Receptor-Associated
Genetic Diseases Using Peripheral Lymphocytes
Yoshitatsu Sei and Sheila M. Muldoon
Mutations in the genes encoding the ryanodine receptor, a Ca2+ release channel, cause autosomal-dominantdiseases of skeletal and cardiac muscle such as malignant hyperthermia (MH), central core disease (CCD),catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia Type 2(ARVD2). Although some of these have congenital myopathies, these ryanodine receptor diseases are allpharmacogenetic. Difficulty in phenotyping and genotyping has significantly slowed the progress in clinical and basicresearch of these genetic diseases. Interestingly, skeletal muscle type (Type 1, RyR1) and cardiac muscle type (Type 2,RyR2) of the ryanodine receptors are expressed in peripheral B and T lymphocytes, respectively. RyR1-mediated Ca2+response in B cells has been used to develop a non-invasive test to predict susceptibility to MH and CCD. Converginglines of evidence now suggest that RyR1-mediated calcium phenotype in B cells or Epstein-Barr virus-transformed Blymphoblasts reflect the RyR1-mediated phenotype in MHS/CCD muscle. Similarly, RyR2 expressed in T cells isavailable to study CPVT/FPVT and ARVD2. Therefore, a ryanodine receptor gene-based system that integratesinformation from cells, transcripts and proteins can be developed using peripheral lymphocytes to study and diagnose theryanodine receptor diseases. Use of genes expressed in lymphocytes can be extended and applied to other genetic diseasesbased on functional genomics.
[Back
to top] The Role of Cytochrome P450 in Herb-Drug Interactions
Modulation of cytochrome P450 (P450) plays a primary role in drug interactions. Polymorphic P450 regulationand expression and environmental exposure are the main causes of variability in human response to xenobioticmodulatory effects. Herbal medicines have been widely used worldwide for centuries. These days, physicians andpharmacists are very concerned about the herb-drug interactions. Herbal medicines such as St. John's wort and EvodiaeFructus have the ability to affect P450 expression and may have the potential to interfere with drug metabolism. Thisarticle briefly reviews recent reports on the in vitro and in vivo effects of natural products on human P450 enzymes andhuman variability in the modulatory response. A better understanding of interactions of herbs with P450 will help theregulation of the use of herbs as drugs and food supplements.