Abstract
Cytochrome P450 (CYP450) enzymes are well-known for their ability to metabolize endogenous and xenobiotic substrates. Fifty-seven functional P450 genes have been identified in humans. This chapter focuses on P450 gene families 1, 2, and 3, as about a dozen enzymes in these families are responsible for the metabolism of the majority of prescription drugs. Genetic polymorphism for these CYP450s can have severe metabolic consequences, since toxicity can be caused by reduced or loss-of-function variant alleles. In addition, drug-drug (DDI), drug-gene (DGI), and drug-drug-gene (DDGI) interactions can significantly impact the ability of individuals to properly metabolize prescriptive medications and may result in adverse drug events (ADEs) or adverse drug reactions (ADRs), which are a major medical concern. Pharmacogenetic testing is a powerful tool in predicting these effects, but there are complicating issues, e.g., substrate specificity, enzyme promiscuity, phenoconversion, epigenetics, heterogeneity of CYP450 enzyme activity in different organs, altered sensitivity to inhibition, and interindividual or interethnic variations in metabolic ability. The best way to estimate metabolic rates is by combining genoty**, phenoty**, and therapeutic drug monitoring, in addition to carefully observing and listening to the patient.
Similar content being viewed by others
Abbreviations
- ADE:
-
Adverse Drug Event
- ADR:
-
Adverse Drug Reaction
- CYP450:
-
Cytochrome P450
- DDGI:
-
Drug-Drug-Gene Interaction
- DDI:
-
Drug-Drug Interaction
- DGI:
-
Drug-Gene Interaction
- EM:
-
Extensive Metabolizer
- EPS:
-
Extrapyramidal Symptoms
- IM:
-
Intermediate Metabolizer
- PharmVar:
-
Pharmacogene Variation Consortium
- SNP:
-
Single Nucleotide Polymorphism
- SSRI:
-
Selective Serotonin Re-uptake Inhibitor
- UM:
-
Ultrarapid Metabolizer
References
Andreassen OA, MacEwan T, Gulbrandsen AK et al (1997) Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients. Psychopharmacology 131:174–179
Armstrong M, Daly AK, Blennerhassett R et al (1997) Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype. Br J Psychiatry 170:23–26
Azhar MZ, Varma SL (1992) Akathisia-induced suicidal behaviour. Eur Psychiatry 7(5):239–241
Bertilsson L, Dahl ML, Tybring G (1997) Pharmacogenetics of antidepressants: clinical aspects. Acta Psychiatr Scand Suppl 391:14–21
Björkenstam C, Möller J, Ringbäck G et al (2013) An association between initiation of selective serotonin reuptake inhibitors and suicide – a Nationwide register-based case-crossover study. PLoS One 8(9):e73973
Bonder MJ, Kasela S, Kals M et al (2014) Genetic and epigenetic regulation of gene expression in fetal and adult human livers. BMC Genomics 15(1):860
Bowers MB, Swigar ME (1988) Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol 8:417–421
Breggin PR (2003) Suicidality, violence, and mania caused by selective serotonin reuptake inhibitors: a review and analysis. Int J Risk Saf Med 16:31–49
Breggin PR (2006a) How GlaxoSmithKline suppressed data on Paxil-induced akathisia: implications for suicidality and violence. Ethical Hum Psychol Psychiatry 8(2):91–100
Breggin PR (2006b) Court filing makes public my previously suppressed analysis of Paxil’s effects. Ethical Hum Psychol Psychiatry 8(1):77–84
Breggin PR (2008) Medication madness. St. Martins Press, New York
Brosen K (1990) Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet 18(3):220–239
Cipriano L (2006) Anti-depressant may cause homicidal feelings. July 12 Available via: https://www.newschannel10.com/story/5138519/anti-depressant-may-cause-homicidal-feelings. Accessed 25 Feb 2022
Conrado DJ, Rogers HL, Zineh I et al (2013) Consistency of drug–drug and gene–grug interaction information in US FDA-approved drug labels. Pharmacogenomics 14(2):215–223
Crowner ML, Douyon R, Convit A et al (1990) Akathisia and violence. Psychopharmacol Bull 26(1):115–117
Damluij NF, Ferguson JM (1988) Parodoxical worsening of depressive symptomatology caused by antidepressants. J Clin Psychopharmacol 8(5):347–348
Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3(6):561–597
DeSwarte RD (1986) Drug allergy: an overview. Clin Rev Allergy 4:143–169
Eikelenboom-Schieveld SJM, Fogleman JC (2021) Psychoactive medication, violence, and variant alleles for cytochrome P450 genes. J Pers Med 11(426):1–16
Eikelenboom-Schieveld SJM, Lucire Y, Fogleman JC (2016) The relevance of cytochrome P450 polymorphism in forensic medicine and akathisia-related violence and suicide. J Forensic Legal Med 41:65–71
FDA (2004) Revisions to product labeling. Available via: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications. Accessed 8 Jan 2022
FDA (2007) Revisions to product labeling. Available via: https://www.fda.gov/media/77404/download. Accessed 10 Mar 2022
Flockhart D, Rae JM (2003) Cytochrome P450 3A pharmacogenetics: the road that needs traveled. Pharmacogenomics J 3:3–7
Geadigk A (2018) Pharmacogene Variation Consortium. Available via: http://www.pharmvar.org. Accessed 20 Feb 2022
George J, Murray M, Byth K et al (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 21(1):120–128
Gill M, Hawi Z, Webb M (1997) Homozygous mutation at cytochrome P4502D6 in an individual with schizophrenia: implications for antipsychotic drugs, side effects and compliance. Ir J Psychol Med 14(1):38–39
Hall RCW, Zisook S (1981) Parodoxical reactions to benzodiazepines. Br J Clin Pharmacol 11:99–104
Hamilton MS, Opler LA (1992) Akathisia, suicidality and fluoxetine. J Clin Psychiatry 53:401–406
Healy D, Farquhar G (1998) Immediate effects of Droperidol. Hum Psychopharmacol 13:113–120
Healy D, Herxheimer A, Menkes DB (2006) Antidepressants and violence: problems at the interface of medicine and law. PLoS Med 3(9):e372
Hocum BT, White JR, Heck JW et al (2016) Cytochrome P-450 gene and Drug interaction analysis in patients referred for Pharmacogenetic testing. Am J Health Syst Pharm 73(2):61–67
Hoffman MF, Preissner SC, Nickel J et al (2014) The transformer database: biotransformation of xenobiotics. Nucleic Acids Res 42:D1113–D1117
Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5(1):6–13
Ingelman-Sundberg M, Sim SC (2010) Pharmacogenetic biomarkers as tools for improved drug therapy. Biochem Biophys Res Commun 396:90–94
Ji Y, Skierka J, Blommel J et al (2016) Preemptive Pharmacogenomic testing for precision medicine: a comprehensive analysis of five actionable Pharmacogenomic genes using next-generation DNA sequencing and a customized CYP2D6 genoty** Cascade. J Mol Diagn 18(3):438–445
Jokinen J, Boström A, Åsberg M et al (2018) Severity of suicide attempt is associated with epigenetic and transcriptional changes in the CYP2D6Gene. Biol Pyschiatry 83:S373
Kalow W (2006) Pharmacogenetics and pharmacogenomics: origin, status, and the Hope for personalized medicine. Pharmacogenomics J 6:162–165
Kirchheiner J, Nickchen K, Bauer M et al (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9(5):442–473
Kupelian D (2010) How evil works. Republic Book Publishers, New York
Lamba V, Lamba J, Yasuda K et al (2003) Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive Androstane receptor) expression. J Pharmacol Exp Ther 307(3):906–922
Lane RM (1998) SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol 12(2):192–214
Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients. JAMA 279(15):1200
Loomis WF (1988) Four billion years. Sinauer Associates, MA
Lucire Y, Crotty C (2011) Antidepressant-induced akathisia-related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family. Pharmgenomics Pers Med 4:65–81
Ma Q, Lu AYH (2008) The challenges of dealing with promiscuous drug-metabolizing enzymes, receptors and transporters. Curr Drug Metab 9(5):374–383
Mancuso CE, Tanzi MG, Gabay M (2004) Paradoxical reactions to benzodiazepines. Pharmacotherapy 24(9):1177–1185
Marcucci C (2015) A case approach to perioperative drug-drug interactions. Springer, New York
McKinnon RA, Sorich MJ, Ward MB (2008) Cytochrome P450 part 1: multiplicity and function. J Pharm Pract Res 38(1):55–57
Moore TJ, Glenmullen J, Furberg CD (2010) Prescription drugs associated with reports of violence towards others. PLoS One 5(12):e15337
Muroi Y, Saito T, Takahashi M et al (2014) Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-Desmethyltamoxifen 4-hydroxylation activity. Drug Metab Pharmacokinet 29(5):360–366
Nebert DW, Gonzales FJ (1985) CytochromeP450 gene expression and regulation. Trends Pharmacol Sci 6:160–164
Nebert DW, Adesnik M, Coon MJ, Estabrook RW, Gonzales FJ, Guengerich FP, Gunsalus IC, Johnson EF, Kemper B, Levin W, Phillips IR, Sato R, Waterman MR (1987) The CYP450 gene superfamily: recommended nomenclature. DNA 6(1):1–11
Nishimura M, Yaguti H, Yoshitsugu H et al (2003) Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by highÂsensitivity realÂtime reverse transcription PCR. Chem Pharm Bull 123(5):369–375
Ortiz de Montellano PR (2015) Cytochrome P450: structure, mechanism and biochemistry, 4th edn. Springer, Heidelberg
Out HJ, Van Meurs P, Van Olden R (2014) Handboek Farmaceutische Geneeskunde. Bohn Stafleu van Loghum, Houten
Padmanabhan S (2014) Handbook of pharmacogenomics and stratified medicine. Elsevier, San Diego
Peng L, Zhong X (2015) Epigenetic regulation of drug metabolism and transport. Acta Pharm Sin 5(2):106–112
Phillips KA, Veenstra DL, Oren E et al (2001) Potential role of pharmacogenomics in reducing adverse drug reactions. A systematic review. JAMA 286(18):2270–2279
Piatkov I (2009) Cytochrome P450 loss-of-function polymorphism genoty** on the Agilent bioanalyzer and clinical application. Pharmacogenomics 10(12):1987–1994
Preissner SC, Hoffmann MF, Preisnner R et al (2013) Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PLoS One 8(12). https://doi.org/10.1371/journal.pone.0082562
Preskorn S (2018) Drug-drug interactions. Professional Communications, West Islip
Preskorn SH, Kane CP, Lobello K et al (2013) Cytochrome P450 2D6 Phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry 74(6):614–621
Rampling D (1978) Aggression: a parodoxical response to tricyclic antidepressants. Am J Psychiatry 135(1):117–118
Sakuyama K, Sasaki T, Ujiie S et al (2008) Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57). Drug Metab Dispos 36(12):2460–2467
Sandson NB (2002) Drug-drug interaction primer. American Psychiatric Publishing, Arlington
Schulte JL (1985) Homicide and suicide associated with akathisia and haloperidol. Am J Forensic Psychiatry 6(2):3–7
Shah RR, Smith RL (2014) Addressing Phenoconversion: the Achilles’ heel of personalized medicine. Br J Clin Pharmacol 79(2):222–240
Shah R, Gaedigk A, LLerena A et al (2016) CYP450 genotype and Pharmacogenetic association studies: a critical appraisal. Pharmacogenomics 17(3):259–275
Shear MK, Frances A, Weiden P (1983) Suicide associated with akathisia and depot Fluphenazine treatment. J Clin Psychopharmacol 3(4):235–236
Short TG, Forrest P, Gattetly DC (1987) Paradoxical reactions to Bezodiazepines–a genetically determined phenomenon? Anaesth Intensive Care 15(3):330–345
Spinelli MG (2004) Infanticide. JAMA 3(1):2157–2158
Suri A, Bramer SL (1999) Effect of omeprazole on the metabolism of Cilostazol. Clin Pharmacokinet 37:53–59
Verbeurgt P, Mamiya T, Oesterheld J (2014) How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genoty**. Pharmacogenomics 15(5):655–665
Vet NJ, De Hoog M, Tibboel D et al (2011) The effect of inflammation on drug metabolism: a focus on pediatrics. Drug Discov Today 16(9/10):435–442
Wynn GH, Oesterheld JR, Cozza KL et al (2009) Clinical manual of drug interaction principles for medical practice. American Psychiatric Publishing, Arlington
Xu C, Li CY-T, Kong A-N (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 28(3):249–268
Yamazaki H (2014) Fifty years of cytochrome P450 research. Springer, Tokyo
Yoo H-D, Cho H-Y, Lee Y-B (2009) Population pharmacokinetic analysis of Cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1. Br J Clin Pharmacol 69(1):27–37
Zackrisson AL (2009) Pharmacogenetics from a forensic perspective: CYP2D6 and CYP2C19 genotype distributions in autopsy cases. Available via: http://www.diva-portal.org/smash/get/diva2:213011/FULLTEXT01.pdf. Accessed 1 Mar 2022
Zackrisson AL, Lindblom B, Ahlner J (2009) High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating Ultrarapid metabolism among suicide cases. Clin Pharmacol and Ther 88(3):354–359
Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138(1):103–141
Zanger UM, Klein K, Thomas M, Rieger JK, Tremmel R, Kandel BA, Klein M, Magdy T (2014) Genetics, epigenetics, and regulation of drug-metabolizing cytochrome P450 enzymes. Clin Pharmacol Ther 95(3):258–261
Zhang J (2003) Evolution by gene duplication: an update. Trends Ecol Evol 18(6):292–298
Zhou SF (2009) Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet 48(11):689–723
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this entry
Cite this entry
Eikelenboom-Schieveld, S.J.M., Fogleman, J.C. (2022). Cytochrome P450 Genes: Their Role in Drug Metabolism and Violence. In: Martin, C., Preedy, V.R., Patel, V.B. (eds) Handbook of Anger, Aggression, and Violence. Springer, Cham. https://doi.org/10.1007/978-3-030-98711-4_84-1
Download citation
DOI: https://doi.org/10.1007/978-3-030-98711-4_84-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-98711-4
Online ISBN: 978-3-030-98711-4
eBook Packages: Springer Reference Behavioral Science and PsychologyReference Module Humanities and Social SciencesReference Module Business, Economics and Social Sciences