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 Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse 

IMAS. Institut. Municipal. d’Investigació Mèdica. . IMIM.  Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse . Rafael de la Torre, PharmD, PhD Unitat de Recerca en Farmacologia. Institut Municipal d’Investigació Mèdica (IMIM). CEXS, Universitat Pompeu Fabra, Barcelona).

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 Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse 

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  1. IMAS Institut Municipal d’Investigació Mèdica . IMIM  Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse  Rafael de la Torre, PharmD, PhD Unitat de Recerca en Farmacologia. Institut Municipal d’Investigació Mèdica (IMIM). CEXS, Universitat Pompeu Fabra, Barcelona) International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  2. Contribution of genetics to multifactorial diseases • Debate about the introduction THC in therapeutics and risk factors associated to its use (seminar). Among them there is an increased risk for developing schizophrenia in predisposed subjects. • In a Toxicology examination at UPF School of Biology, students were requested to discuss these risk factors. Some students wrote: • Candidate patients should be genotyped for schizophrenia meaningless • A psychiatric exploration would be more meaningful International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  3. (25-50%) • DNA • SNPs • other polymorphisms metabolism neuroadaptation withdrawal (very high) (very high) (very high) Factors Contributing to Vulnerability to Develop a Specific Addiction International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 J Pollock-NIDA (modified)

  4. Social Phobias Social Phobias Alcohol and Alcohol and 13 13 13 – – – – 20 20 20 20 Alcohol and Alcohol and Years Years Years Years Drug Use Drug Use Panic Disorder Panic Disorder Drug Use Drug Use Disorders Disorders Disorders Disorders Bipolar Disorder Bipolar Disorder Age Age Age Age Age Age Age Age Age Age Age Age Age Age Eating Disorders 10 10 10 10 – – – – 13 13 13 13 Years Years Years Years Obsessive Compulsive Disorders - - - Anti - social Behavior - - - 5 5 5 5 – – – – 10 10 10 10 Conduct Disorder Brain Brain Brain Brain Years Years Years Years Depression Disorders Disorders Disorders Disorders Anxiety Infancy to Infancy to Infancy to Infancy to Attention Deficit Hyperactivity Disorder 5 Years 5 Years 5 Years 5 Years Autism Age of Onset of Brain Disorders The link between schizophrenia and cannabis consumption seems to be strongly associated to the age of first consumption (i.e. >15y vs. <15y) International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  5. Drug Addiction: A Developmental Perspective metabolism neuroadaptation withdrawal International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  6. Why we are concerned about genes in the context of drug addiction? • Better understanding of environmental factors in addiction • Will improve treatment interventions • Facilitate understanding the neurobiology of addiction and drug abuse International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  7. Substance abuse vulnerability loci: converging genome scanning data • There are 15 reproducible chromosomal loci identified, • good candidates to harbor allelic variants that alter • human substance abuse vulnerabilities. Polygenic inheritance for substance abuse vulnerability Knowledge of genotypes at loci containing vulnerability alleles could improve the management of vulnerable individuals and thus the cost-effectiveness of addiction prevention and treatment International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 Uhl GR, TRENDS in Genetics 2002; 18:420-5

  8. Genes Canditates Associated with Addictive Diseases International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  9. ORPM1 gene Ikeda K Trends Pharmacol Sci. 2005;26:311-7. International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  10. ORPM1 gene and the A118G variant (I) • >100 polymorphisms in humans • More abundant in the non-protein-coding regions • 10 SNPs in ORPM1 translated region • The A118G variant is the most frequent coding region variant in most samples • 45% in Asians • 5-25% in European and African-American • The A118G variant is a missense SNP that changes the N-terminal region amino acid (Asn40Asp)decrease in the number of sites for N-linked glycosilation of the MOP receptor from 5 to 4. • The A118G SNP increases three folds the affinity of b-endorphin for MOR International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  11. ORPM1 gene and the A118G variant (II) • Associated to vulnerability to dependence on addictive substances • Opiates • Alcohol • Poly-drug use • Decreased sensitivity to major active morphine metabolite after its p.o. administration morphine-6-O-glucuronide • Alteration to stressors of the HPA axis International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  12. ORPM1 gene and the A118G variant (III) Vulnerability to Dependence on Opiates and Alcohol • Study in a Swedish population (little admixture over the past centuries) • Allelic frequency of the 118G allele 11% • Opiates • 120 control subjects vs. 67 opiate dependent subjects • Association between the 118G allele and genotype and heroin addiction (OR=2.72, p=0.0025 and OR=2.97, p=0.0031) • Attributable risk due to genotypes with a G allele was 21.0% (95% CI 6.0-34.0%) • Alcohol • 120 control subjects vs. 193 alcohol dependent subjects • Association between the 118G allele and genotype and heroin addiction (OR=1.92, p=0.0074 and p=0.095) • Attributable risk due to genotypes with a G allele was 11.1% (95% CI 3.6-18.0%) Bart G. Mol Psychiatry 2004;9: 547-9 and Neuropharmacology 2005;30:417-22 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  13. ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT) • Rationale: • beta-endorphin is released following acute and short-term nicotine exposure • The mu-opiod receptor (OPRM1) related to reward effects of beta-endorphin • The Asp40 variant (A118G) increases binding affinity for beta-endorphin, and is found in 25-30% of subjects with European ancestry • Which is the clinical response to NRT as a function of the Asp40 variant? • Two treatments compared: transdermal nicotine (TN) vs. nicotine nasal spray (NS) • Population of 320 smokers (TN=153, NS=167), genotyped for the A118G International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  14. ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT) • Results: • Smokers carrying the Asp40 variant when compared to homozygous for Asn40 were more likely • to be abstinent at the end of treatment (52%vs.33%), • to report less mood disturbances • to gain less weight (0.7vs.2.1 kg) • Effects more pronounced on subjects treated with the high dose of TN • Differences between genotype equivalent to comparison of placebo vs. NRT Lerman C Pharmacogenomics J. 2004;4:184-192 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  15. ORPM1 gene and the A118G variant (IV) Naltrexone (NTX) and Alcoholism • Rationale: • beta-endorphin compensation model alcoholics have a relative deficiency in endogenous opioids when confronted with stressful situations. • Alcohol increase endogenous opioids and this may account for its reinforcing properties • The Asp40 variant (A118G) increases binding affinity for beta-endorphin, and is found in 25-30% of subjects with European ancestry • Which is the clinical response to naltrexone as a function of the Asp40 variant? • Two treatments compared: NTX vs. placebo • Population of 82 patients treated with NTX vs. 59 treated with placebo International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  16. ORPM1 gene and the A118G variant (IV) Naltrexone (NTX) and Alcoholism • Results: • Alcoholics treated with NTX carrying the Asp40 variant when compared to homozygous for Asn40 had lower rates of relapse (p=0.04) and longer time to return to heavy drinking • Patients homozygous for Asn40 treated with NTX were not different from placebo Oslin DW Neuropsychopharmacology 2003;28:1546-52 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  17. Potential role of pharmacogenetics of CYP enzymes in drug abuse, dependence and neurotoxicity • The CYP superfamily of heme-based oxidases are genetically variable and are involved in the metabolic detoxification / activation of a number of drugs of abuse • Hypothesis: differences in pattern of drug metabolism among individuals and across ethnic groups due to genetic variability are likely to affect the risk of drug dependence and neurotoxicity • The effects of genetically variable metabolism on drug dependence depends on whether the parent drug, metabolite(s) or both are responsible for its addictive properties • The effects of genetically variable metabolism on neurotoxicity depends on the fraction of the drug bioactivated to neurotoxic species International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  18. Potential role of pharmacogenetics of CYP enzymes in drug abuse and dependence • Non functional allelic variants or allelic variants associated with enzymes with low activity might be associated with an increased drug abuse liability or alternatively might protect against drug dependence • CYP2D6 (codeine, methamphetamine) • CYP2A6 (nicotine) International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  19. In subjects with functional alleles Higher drug abuse liability Higher analgesic effects In subjects with non-functional alleles Higher drug abuse liability CYP2D6 and drug abuse liability International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  20. CYP2A6 and nicotine dependence No CYP2A6 activity, Homozygous for CYP2A6*2, CYP2A6*4, and CYP2A6*5 inactive alleles; 50% CYP2A6 activity, heterozygous for inactive alleles and homozygous for any combination of reduced activity alleles CYP2A6*6, CYP2A6*7, CYP2A6*9, CYP2A6*10, and CYP2A6*12; 75% CYP2A6 activity, heterozygous for reduced activity alleles; Normal (100%) CYP2A6 activity, remaining percentage of those not included in any other group. International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 Malaiyadi V, CPT, 2005,77, 145-58

  21. CYP2A6 and nicotine dependence • Hypothesis: Slow inactivators of nicotine • Reduced risk for smoking • Lower amount smoked • Altered smoking intensity (first smoking) • Increased quitting • Lower risk of lung cancer (inhibition of pro-carcinogens bioactivation) Some conflicting results, but several experimental studies support the hypothesis CYP2A6 phenocopying as a novel approach for smoking reduction and cessation International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  22. Potential role of pharmacogenetics of CYP enzymes in drug abuse toxicity and neurotoxicity MDMA AND PHARMACOGENETICS International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  23. MDMA and pharmacogenetics • Do genetic polymorphism in enzymes involved in MDMA metabolic disposition contribute to any extend to acute toxic effects? • In females of Dark Agouti rats, deficient in the CYP2D1 isozyme a drastic reduction of the rate of O-demethylenation of MDMA when compared to SD rats was observed. CYP2D6 MDMA • In yeast microsomes expressing human CYP2D6, it was demonstrated that this isozyme regulated partially the O-demethylenation of MDMA. At high MDMA concentrations other isozymes of cytochrome P450, CYP1A2, CYP3A4, CYP2B6 contribute to this metabolic reaction HHMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  24. MDMA pharmacogenetics and acute toxicity (i) • CYP2D6 is a polymorphic enzyme in humans with several allelic variants some of them leading to non-functional or partially functional enzymes. • Several phenotypes are present in the population: extensive(homozygous for functional alleles), intermediate (homozygous partially functional or heterozygous for a non-functional allele), poor (homozygous for non functional alleles) and ultrarapid (gene duplication of functional alleles) metabolizers. • The fact that O-demethylenation of MDMA is regulated partially by CYP2D6 immediately raised the question: To which extend poor metabolizers (PM) are at higher risk of acute toxicity episodes? International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  25. MDMA pharmacogenetics and acute toxicity (ii) • This risk has never been confirmed in humans after CYP2D6 genotyping of MDMA casualties. No bias towards PM subjects has been observed • The fact that O-demethylenation of MDMA is regulated partially by CYP2D6 immediately raised the question: To which extend poor metabolisers (PM) are at higher risk of acute toxicity episodes? Why? International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  26. MDMA metabolic disposition in humans MDMA CYP2D6 HHMA COMT HMMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  27. MDMA INHIBITS ITS OWN METABOLISM Amounts of CYP2D6 in liver are limited and easily saturated Metabolites formation at doses higher than 75 mg is regulated by the dissociation of the carbene complex and independent of the dose International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  28. HMMA MDMA MDMA NON-LINEAR PHARMACOKINETICS MDMA 50 mg MDMA 150 mg MDMA 100 mg International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  29. MDMA NON-LINEAR PHARMACOKINETICS Summary PLASMA URINE International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  30. STUDIES ON THE PHARMACOLOGY OF MDMA IN HUMANSRepeated Doses Clinical Studies • Most MDMA users have more than one dose per rave/session • On the view of the non-linear kinetics of MDMA in humans, are those MDMA users ingesting repeated doses more prone to acute effects than those taking single doses? • Are MDMA users ingesting repeated doses just adjusting pharmacological effects over the time with relatively little risk for acute toxicological effects? International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  31. MDMA metabolic disposition after repeated doses 300 250 200 (second consecutive dose) 150 plasma concentration (µg/L) 100 50 0 0 4 8 12 16 20 24 MDMA (100 mg), two doses taken 24h apart -After the 2nd dose MDMA metabolism is reduced -MDMA accumulates (about 30%, accounting for the overall contribution of CYP2D6 to MDMA disposition) time (h) 300 (first dose) 250 200 150 plasma concentration (µg/L) 100 50 0 0 4 8 12 16 20 24 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 time (h) MDMA HMMA HHMA

  32. Modeling of CYP2D6 inhibition by MDMA • A typical recreational MDMA dose • could inactivate most hepatic CYP2D6 • within an hour • The return to a basal level of CYP2D6 • could take at least 10 days Implications of Mechanism-Based Inhibition of CYP2D6 for the Pharmacokinetics and Toxicity of MDMA. J Yang, M Jamei, A Heydari, K R. Yeo, R de la Torre, M Farré, GT. Tucker, A Rostami-Hodjegan. JPET (2005) in press International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  33. PM (*4/*4) IM (*1/*4) EM (*1/*1) Plasma concentrations over time curves of MDMA, HHMA and HMMA as a function of CYP2D6 genotype MDMA CYP2D6 HHMA COMT HMMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  34. Urinary recovery (0-24h) of MDMA and main metabolites as a function of CYP2D6 genotype EM IM PM International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  35. Phenotypically EM subjects are “converted” to PM subjects after repeated doses 300 250 200 EM subjects (second consecutive dose) 150 plasma concentration (µg/L) 100 PM subjects (any dose) 50 300 0 250 0 4 8 12 16 20 24 time (h) 200 300 concentration (µg/L) 150 EM subjects (first dose) 250 100 200 50 150 plasma concentration (µg/L) 0 100 0 5 10 15 20 25 50 time (h) 0 0 4 8 12 16 20 24 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 time (h) MDMA HMMA HHMA

  36. MDMA pharmacogenetics and acute toxicity (iii) • This risk has never been confirmed in humans after CYP2D6 genotyping of MDMA casualties. No bias towards PM subjects has been observed Why? • Because repeated consumption of MDMA leads to a phenomenon of quasi phenocopying of subjects towards to the PM phenotype independently of the original genotype of subjects • Nevertheless subjects after MDMA ingestion have its CYP2D6 enzyme inhibited until newly enzyme is synthesised and this may lead to acute toxicity episodes as well as pharmacological interactions with drugs co-substrates of this enzyme International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  37. MDMA pharmacogenetics and neurotoxicity (i) • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity? • MDMA in animal models when injected directly into the brain produces 5-HT release but not neurotoxicity. • This observation suggests that MDMA must be metabolized peripherally in order to produce compounds that induce free radical formation and neurotoxicity in the brain International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  38. MDMA pharmacogenetics and neurotoxicity (ii) • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity? • MDMA in animal models gives rise to HHMA in a reaction catalyzed partially by CYP2D1 • HHMA is further metabolized to a compound capable of forming adducts with GSH, electrochemically active via a SOD-sensitive pathway • Therefore there may be a role for CYP2D6 in neurotoxicity as it participates in the bioactivation of MDMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  39. MDMA HHMA quinone HHMA-GSH adduct MDMA METABOLISM FORMATION OF GLUTATHIONE ADDUCTS CYP2D6 SOD-sensitive pathway TJ Monks ,SS Lau, RT Miller ,F Bai,DC Jones Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  40. THIOETHERS OF MDMA AS PUTATIVE TOXIC SPECIES INVOLVED IN NEUROTOXICITY • Able to reproduce acute and long-term effects • Display in the brain a good selectivity for serotonergic axonic terminals • Biosynthesized at the hepatic level • Distributed to the rest of the body by blood circulation • Most likely benefit from glutathione specific transport mechanisms to cross the blood brain barrier International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  41. THIOETHERS OF MDMA ARE FORMED IN VIVO IN RATS As MDMA neurotoxicity depends on its metabolic bioactivation, pharmacogenetics of CYP2D6 becomes relevant again International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 Jones DC JPET 2005; 313: 422-31.

  42. N-Ac-5-[cysteinyl]-HHMA ANALYSIS OF THIOETHERS ADDUCTS OF MDMA 5-[GSH]-HHMA g-glutamyl acetyl 5-[cysteinyl-glycyl]-HHMA glycyl 5-[cysteinyl]-HHMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 Perfetti X et al 2005

  43. THIOETHERS OF MDMA ARE FORMED IN VIVO IN HUMANS LC/MS-MS Assay in human urine As MDMA neurotoxicity depends on its metabolic bioactivation pharmacogenetics of CYP2D6 becomes relevant again N-Ac-5-Cys-HHMA N-Ac-5-Cys-O-Me-HHMA (ISTD) Hypothesis: Are those subjects with more than one functional copy of CYP2D6 gene more prone to develop neurotoxicity? About 1% of the dose (MDMA 75 mg) is recovered in urine as N-Ac-5-Cys-HHMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005 Perfetti X et al 2005

  44. MDMA pharmacogenetics and neurotoxicity (iii) • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity? • MDMA in animal models gives rise to HHMA in a reaction catalyzed partially by CYP2D6 • HHMA is further metabolized to a compound capable of forming adducts with GSH, electrochemically active via a SOD-sensitive pathway • COMT contribution to metabolize HHMA to HMMA may counteract partially bioactivation of HHMA • COMT is a polymorphic enzyme in humans, therefore some genotypes may play a protective role in MDMA neurotoxicity International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  45. PM (*4/*4) IM (*1/*4) EM (*1/*1) Plasma concentrations over time curves of MDMA, HHMA and HMMA as a function of CYP2D6 genotype MDMA CYP2D6 HHMA COMT HMMA International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  46. Comparison of personality characteristics (TCI) ecstasy vs. cannabis vs. control groups ENTE Project p<0.001 p<0.001 NS=novelty seeking ST=self-transcendence International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  47. Control group (n=34) 35,3 20,6 44,1 Drug Users (n=63) COMT phenotypes (activities) vs. genotype - Low – 158 Met/Met - High – 158 Val/Val - Medium –158Val/Met 12,9 37,1 50 COMT Genotype and Drug AbuseENTE Project COMT genotypes associated to high/medium enzyme activities more prevalent among drug users may protect individuals against neurotoxicity p<0.03, higher prevalence of the 158 Val/Val genotype International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  48. Summary • Two genetic polymorphic enzymes contributes to the variability of MDMA disposition in humans: CYP2D6 and COMT • CYP2D6 genotype is less relevant than expected in acute toxicity episodes because the inhibition of this enzyme by MDMA through the formation of an enzyme-metabolite complex • CYP2D6 and COMT participate in the formation and metabolism of HHMA, a MDMA metabolite involved in the formation of thioether adducts, putative neurotoxic species of MDMA • The balance between the activities of both enzymes may determine the susceptibility of MDMA users to develop neurotoxicity with different degrees of severity International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  49. Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse Does it makes sense? …diseases appearing to be "highly amenable to environmental modification“ should take low priority in genomic research. … K. R. Merikangas and N. Risch Science, 2003; 302:599-601 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

  50. Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse Does it makes sense? …addiction is not easily malleable; approximately 90% of smokers who try to quit relapse within a year, with the majority relapsing within a week… Employing the power of genetic studies in understanding the underlying biological, behavioral, and environmental factors will enhance research on etiology, treatment, and prevention for these complex diseases. The diseases given low priority by Merikangas and Risch affect about 30% of the U.S. population; those affected cannot afford to wait when advances in genetics will have a significant public health impact. W Berrettini et al Science 2004;304:1445-1447 International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

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