Pharmacogenetics of Cytochrome P450 & Phase II Enzymes PDF

Pharmacogenetics of Cytochrome P450 and Phase II Drug-Metabolizing Enzymes  Learning Outcomes: By the end of this lecture you should be able to: Explain the role of cytochrome P450 (CYP) enzymes in drug metabolism. Identify key genetic polymorphisms in CYP450 and Phase II enzymes that af...

Pharmacogenetics of Cytochrome P450 and Phase II Drug-Metabolizing Enzymes  Learning Outcomes: By the end of this lecture you should be able to: Explain the role of cytochrome P450 (CYP) enzymes in drug metabolism. Identify key genetic polymorphisms in CYP450 and Phase II enzymes that affect drug metabolism. Summarize the consequences of gentic polymorphism in Cytochrome 450 enzyme system. Discuss clinical implications of genetic polymorphisms in drug metabolism.  Cytochrome P450 Enzymes: Overview Function: Catalyze the oxidation of organic substances; key role in phase I metabolism.Primarily found in liver cells. Clinical Importance: Variability in CYP450 enzyme activity leads to differences in drug clearance and response. 57 Different active genes and 17 Different families. Major Families :CYP1, CYP2 and CYP3 are primarily involved in drug metabolism. CYP2A6, CYP2B6, CYP2C9 ,CYP2C19, CYP2D6, CYP2E1 and CYP3A4 are responsible for metabolizing most clinically important drugs. Everyone has a varying capacity to metabolize a drug through a given pathway. Example: Isoniazid is metabolized in the liver via acetylation. Slow acetylators are prone to peripheral neuritis while fast acetylators are prone to hepatic toxicity.  Consequences of Gentic Polymorphism in Cytochrome 450 Enzyme System Genetic polymorphisms in the Cytochrome P450 (CYP) enzyme system can have a range of consequences due to the crucial role these enzymes play in drug metabolism, hormone synthesis, and the metabolism of various endogenous and exogenous substances. Here are some key consequences: 1. Variable Drug Metabolism 2. Drug Interactions 3. Variability in Drug Response 4. Increased Risk of Adverse Drug Reactions 5. Altered Hormone Levels 6. Impact on Disease Risk 7. Individualized Medicine  1. Variable Drug Metabolism:  If the body metabolizes a drug too quickly, it may not get any benefit from the prescribed dose, the dose may need to be increased to reach a therapeutic effect.  If the body metabolizes a drug too slowly, it stays active longer, and may be associated with side effects.  Because of this, the individual may be one of the following four metabolizer types: 1. Poor metabolizers (PM) have significantly reduced or non-functional enzyme activity. 2. Intermediate metabolizers (IM) have low or reduced enzyme activity. 3. Extensive metabolizers (EM) have normal enzyme activity. 4. Rapid or ultra-rapid metabolizers (RM) have high enzyme activity.  2. Drug Interactions: Variations in CYP enzymes can affect how individuals respond to drug interactions. For example, if one drug affects the activity of a CYP enzyme that metabolizes another drug, it can lead to altered drug levels and potentially adverse effects or reduced efficacy. 3. Variability in Drug Response: Genetic differences can influence individual responses to drugs. For example, some people may experience enhanced or diminished therapeutic effects based on their CYP genotype. 4. Increased Risk of Adverse Drug Reactions: Certain polymorphisms may predispose individuals to a higher risk of adverse drug reactions. For instance, a genetic variant in CYP2D6 can lead to severe reactions to drugs like codeine or tamoxifen.  5. Altered Hormone Levels: CYP enzymes are involved in the metabolism of steroid hormones. Polymorphisms can influence hormone levels and affect conditions related to hormone balance, such as estrogen-related cancers or hormone replacement therapy responses. 6. Impact on Disease Risk: Variations in CYP enzymes can influence susceptibility to diseases by altering the metabolism of carcinogens, toxins, or other environmental factors. For example, certain CYP polymorphisms are linked to an increased risk of developing cancer due to inefficient metabolism of carcinogens. 7. Individualized Medicine: Understanding an individual’s CYP genotype can help tailor drug treatments to improve efficacy and reduce side effects. Pharmacogenetic testing is increasingly used to guide drug prescribing and dosing.  Pharmacogenetic Variability in CYP450 Enzymes Common Polymorphisms: Pharmacogenomics of CYP2C9  CYP2C9 is the most expressed enzyme in the human liver, accounting for the metabolism of approximately 15–20% of prescribed and over-the-counter drugs.  CYP2C9 metabolizes several clinically important drugs, including the antidiabetic drugs tolbutamide and glipizide, the anticonvulsant phenytoin, the anticoagulant warfarin, the antihypertensive drug losartan, the diuretic torasemide, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, piroxicam, tenoxicam, and mefenamic acid.  Drugs with a narrow therapeutic index, such as S-warfarin and phenytoin, can present serious problems in poor metabolizes (PM).  The clinical relevance of CYP2C9 polymorphisms was initiated and identified by two main coding variants, CYP2C9*2 and *3 Alleles. P450s Drug Consequences CYP2C9 Warfarin  Increased risk of bleeding episodes in PMs caused by reduced metabolism of warfarin and therefore increased warfarin concentration at normal dose. Phenytoin  Increased risk of ataxia, unconsciousness, and mental confusion in PMs caused by increased phenytoin level. Glimepiride,  Increased risk potential of hypoglycemia in PMs tolbutamide, due to increased drug level and low blood sugar glyburide, level. glipizide N.B: The 2 most common reduced-function variants are *2 (rs1799853) and *3 (rs1057910). The CYP2C9*2 allele reduces warfarin clearance by 30% and the *3 allele by 90%), which translate into 19% and 33% reductions per allele in warfarin dose requirements compared to noncarriers.  Pharmacogenomics of CYP2C19 The cytochrome P450 CYP2C19 is a clinically important enzyme that metabolizes several drugs such as the antiulcer drug omeprazole, the anticonvulsant mephenytoin, the antimalarial proguanil, the anxiolytic drug diazepam, and certain antidepressants such as citalopram, imipramine, amitriptyline, and clomipramine P450s Drug Consequences CYP2C19 Diazepam  Increased risk of sedation time and unconsciousness in PMs caused by prolonged half-life of diazepam. Omeprazole,  Increased cure rates due to increased half-life of the Pantoprazole, parent drugs in PMs. Lansoprazole  Decreased cure rates in Ems(Extensive metabolizer) and URMS(Ultrapid metabolizer). Clopidogrel  Decreased response to clopidogrel in PMs due to low transformation into active metabolite (Thiol metabolite).  CYP2D6 Polymorphism CYP2D6 is one of the most polymorphic CYP450 and metabolizes approximately 20% of prescribed drugs. Substrates of CYP2D6 include antipsychotic drugs (haloperidol, clozapine, and risperidone), antiarrhythmic agents (flecainide), tricyclic antidepressants (imipramine, clomipramine, nortriptyline, and amitriptyline), βadrenoreceptor antagonists (metoprolol, propranolol, bupranolol, and carvedilol), opioids (codeine and tramadol), and the estrogen receptor antagonist tamoxifen P450s Drug Consequences CYP2D6 Imipramine,  Diminished response to the drugs in trimipramine, Ums. doxepin  increased risk of adverse effects in the CNS and others in PMs. Perphenazine,  Diminished response to the drugs in thioridazine, Ums. olanzapine  Increased risk of extrapyramidal side effect and others in PMs. Tamoxifen  Poor drug efficacy in PMs due to low transformation into the active metabolite (Endoxifen). 13 CYP2D6 Codeine  Codeine is a prodrug. It must be metabolized into morphine for activity.  Increased risk of adverse effects in UMs due to high concentration of its active metabolite (morphine).  7% of Caucasians are missing one copy of the CYP2D6 gene (PMs). So, Codeine does not work effectively in these individuals. 14  Tramadol  N.B. the active metabolite of tramadol (O- CYP2D6 desmethyltramadol) is responsible for its analgesic effect and side effect.  Increased risk of respiratory depression or severe nausea in UMs due to high concentration of the active metabolite.  Decreased analgesic effect in PMs. Carvedilol,  Increased risk potential of various side effects in metoprolol, PMs due to reduced metabolism and increased propranolol, drug concentrations. timolol  Pharmacogenomics of CYP1A2  CYP1A2 is involved in the metabolism of coffee, estrogen, clozapine, theophylline, olanzapine, and certain procarcinogens.  The enhanced induction of this enzyme i.e. in UMs, altered therapeutic outcomes or increased risk of certain cancers.  Example: Coffee is a major source of caffeine, which is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme.  Individuals who are homozygous for the CYP1A2*1A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are "slow" caffeine metabolizers  CYP2B6 is involved in the metabolism of bupropion, efavirenz, nevirapine, cyclophosphamide, and ifosfamide.  Several HIV patients receiving efavirenz experience central nervous system side effects, which are suggested to be from the varying concentration of efavirenz in plasma.  Pharmacogenomics of CYP2A6  CYP2A6 metabolizes nicotine, cotinine (Nicotine metabolites), Methyl-n-amylnitrosamine (MNAN) is a potential carcinogen ,and nicotine derived nitrosamine ketone (NNK).  Therefore, UMs have been suggested to experience increased susceptibility to nicotine addiction, which has been proposed to be linked to the increased risk of smoking related cancers.  While PMs Individuals carrying inactive CYP2A6 have reduced nicotine metabolism, and less likely to become smokers, and if they did, they smoked fewer cigarettes per day. Since, Increased levels of nicotine produced harmful side effects that discouraged initiation of smoking.  Role of Phase II Biotransformation in Drug Elimination  There are several classes of phase II biotransformation enzymes that catalyze drug conjugation reactions.  Among the most important are the UDP glucuronosyltransferases (UGTs) (metabolism of bilirubin, NSAIDs)., sulfotransferases (SULTs), Nacetyltransferases (NATs) Acetylation (metabolism of isoniazid), and glutathione Stransferases (GSTs). These enzymes contribute to most clearance pathways that exist for most drugs.  Thiopurine-S-methyltransferase (TPMT): Detoxification of reactive species  The acylCoA synthetase medium chain family members that act in conjunction with acylCoA: amino acid N-acyltransferases to generate amino acid conjugates.  Finally, there is a group of enzymes such as catechol Omethyltransferase (COMT) and other methyltransferases that are functionally important in the clearance of neurotransmitters or other molecules of endogenous importance.