The enzymes of the cytochrome P450 superfamily play a central role in the metabolism of endogenous substrates, environmental toxins, carcinogenic substances, and a wide variety of pharmaceuticals. These enzymes are primarily expressed in the liver and function as monooxygenases in Phase I reactions. Based on amino acid sequence homologies, the cytochrome P450 gene superfamily is divided into 36 gene families, which are further subdivided into subfamilies. Within these subfamilies, the clinical significance and association of genetic variants with altered enzyme activities—particularly for CYP2D6, CYP2C19, and CYP2C9—are well characterized.
Changes in enzymatic activity of Phase I or Phase II enzymes can be acquired (e.g., liver insufficiency) or congenital. Congenital changes are based on genetic variants that lead to reduced or absent enzyme activity, resulting in slower substrate metabolism (“poor metabolizer phenotype”). Conversely, gene variants have been described that lead to increased enzyme activity, resulting in rapid substrate metabolism (“ultrarapid metabolizer phenotype”). The metabolizer phenotype influences the efficacy and tolerability of drugs.
Enzymes listed below:
CYP2D6
CYP2D6 metabolizes approximately 20–30% of the most commonly used drugs, including a large proportion of psychotropic medications and neuroleptics, as well as various cardiovascular drugs. It is also involved in the prodrug activation of tramadol, oxycodone, and tamoxifen. Both the “poor metabolizer” and “ultrarapid metabolizer” phenotypes have been described for this enzyme.
Various variants in the CYP2D6 gene lead to reduced or absent enzyme activity, resulting in the “intermediate” or “poor metabolizer” phenotypes. In both phenotypes, adverse drug reactions may occur when CYP2D6 substrates are administered at standard doses. Dose reduction in such cases may help minimize side effects and thereby improve therapeutic outcomes. Dosage recommendations for various drugs can be found in the CPIC, CPNDS, and DPWG guidelines.
In contrast, for prodrugs that are activated by CYP2D6 into their active metabolites (e.g., tramadol, tamoxifen), therapy resistance may occur in poor metabolizers.
In the Central European population, the alleles CYP2D6*3, *4, *5, *6, *9, and *41 are particularly relevant. The proportion of “poor metabolizers” within the Caucasian population is about 7%, while “intermediate metabolizers” account for around 40%.
The “ultrarapid metabolizer” phenotype (CYP2D6*XN allele) shows increased enzyme activity and is associated with therapy resistance. When CYP2D6 substrates are administered at standard doses, sufficient efficacy is often not achieved (non-responder type; incidence approx. 7%). In such cases, increasing the dose may improve therapeutic success.
References
Nofziger et al., Clin Pharmacol Ther 2020;107(1):154-170; Taylor et al., Genes (Basel) 2020 Oct 30;11(11):1295
CYP2C19
The enzyme CYP2C19 metabolizes active ingredients such as mavacamten, proton pump inhibitors, and various psychotropic drugs. It also mediates the prodrug activation of clopidogrel. In addition, CYP2C19 provides an alternative metabolic pathway for CYP2D6 substrates. Both the “poor” and “ultrarapid metabolizer” phenotypes are known for CYP2C19.
Various genetic variants lead to either a loss, reduction, or increase in enzyme activity. The CYP2C19*2 allele is the most common allele in the Caucasian population associated with reduced enzyme activity. Approximately 5% of the population are classified as "poor metabolizers," while 20% exhibit the "intermediate metabolizer" type. Both phenotypes may develop adverse drug reactions when given standard doses of CYP2C19 substrates. A dose reduction can reduce side effects in these cases and thus enhance treatment success. The CYP2C19*17 allele is associated with increased substrate metabolism and occurs in about 20% of the Caucasian population. This phenotype often experiences no effect under standard dosing of CYP2C19 substrates (non-responder type). A dose adjustment can improve treatment success in these cases.
Dosage recommendations for various substances can be found in the relevant CPIC and DPWG guidelines.
References
Swen et al. 2011, Clin Pharmacol Ther 89:662 / Li-Wan-Po et al. 2010, Br J Clin Pharmacol 69:222 / Rudberg et al. 2008, Clin Pharmacol Ther 83:322 / Seeringer et al. 2008, Internist 49:877 / Sim et al. 2006, Clin Pharm Ther 79:103
CYP2C9
CYP2C9 is involved in the oxidative metabolism of non-steroidal anti-inflammatory drugs (e.g., diclofenac, ibuprofen), antidiabetic agents, phenytoin, and coumarin derivatives. Currently, only the “poor metabolizer” phenotype is described for CYP2C9.
Variants in the CYP2C9 gene are associated with reduced enzyme activity, with the presence of the CYP2C9*2 and CYP2C9*3 alleles being the most common genetic causes of enzyme deficiency. In the Caucasian population, the proportion of “poor metabolizers” is approximately 4%, while the “intermediate metabolizer” type accounts for about 30%. Both phenotypes may develop adverse drug reactions when treated with standard doses of CYP2C9 substrates. A dose reduction can enhance treatment success in these cases.
Dosage recommendations for various substances can be found in the CPIC, CPNDS, and DPWG guidelines.
References
Sangkuhl et al., Clin Pharmacol Ther. 2021 Sep;110(3):662-676 / Swen et al. 2011, Clin Pharmacol Ther 89:662
CYP3A4
CYP3A4 participates in the oxidative metabolism of a wide range of drugs, endogenous steroids, and xenobiotics. Alleles with altered enzyme activity have been described for this enzyme. However, interindividual differences in metabolic capacity are primarily due to enzyme induction or inhibition caused by co-medication or food interactions. Some genetic variants of CYP3A4 are associated with altered enzyme activity. Among these, the CYP3A4*22 allele is currently considered to have the highest clinical relevance from a genetic perspective. Various studies have shown that this allele is associated with reduced enzyme activity, resulting in elevated drug levels for certain substrates—particularly tacrolimus. Testing for this allele is part of routine diagnostics.
Important Note:
Since the concurrent intake of medications, herbal products, or foods can lead to the induction or inhibition of CYP3A4, potential drug and food interactions should be ruled out before conducting genetic testing.
References
Wang and Sadee 2016, Pharmacogenet Gen ; 26(1): 40–43 / Perera 2010, Expert Opin Drug Metab Toxicol. 6:17 / Lamba et al. 2002, Adv Drug Deliv Rev 54:1271 / Dai et al. 2001, J Pharmacol Exper Ther 299:825
CYP3A5
The enzyme CYP3A5 is expressed in only a minority of the population. Up to 90% of the Caucasian population are classified as “non-expressor phenotype” due to a polymorphism in the gene (CYP3A5*3 allele), resulting in very low CYP3A5 enzyme activity. Individuals with at least one CYP3A5*1 allele show increased enzyme expression (expressor phenotype), which can lead to insufficient therapeutic levels of CYP3A5 substrates and treatment failure.
In carriers of this allele, CYP3A5 can account for up to 50% of hepatic CYP3A content, leading to a faster metabolism of CYP3A substrates. Patients with the CYP3A5*1 genotype often show a reduced response to CYP3A5-dependent medications compared to those with the CYP3A5*3/*3 genotype.
CYP3A5 is involved in both the metabolism and synthesis of cholesterol, steroid hormones (such as testosterone, progesterone, androstenedione), and other lipids, and also in the breakdown of a variety of drugs (e.g., cyclosporine, various statins, psychotropic drugs, and chemotherapeutic agents).
There is evidence that CYP3A5 plays an important role in the metabolism of tacrolimus, and that the effectiveness of this drug may be reduced in carriers of the CYP3A5*1 allele.
Dosage recommendations can be found in the CPIC and DPWG guidelines for tacrolimus and CYP3A5.
References
Rodriguez-Antona et al., Clin Pharmacol Ther . 2022 Dec;112(6):1159-1171
CYP1A2
CYP1A2 is involved in the oxidative metabolism of several drugs and environmental toxins. Interindividual differences in metabolic capacity are primarily due to enzyme inhibition or induction caused by co-medication, food intake, or cigarette smoke. Some variants in the CYP1A2 gene also lead to altered enzyme activity. In particular, the CYP1A2*1F allele is associated with increased inducibility of the enzyme and an accelerated metabolism of CYP1A2 substrates. This allele is found at a high frequency—approximately 70%—in the Caucasian population. Additionally, there are known variants that result in reduced enzyme activity. Detection helps clarify low therapeutic levels of CYP1A2 substrates. Knowing the CYP1A2 genotype can be used to adjust the dosage in therapies involving CYP1A2-dependent drugs.
References
Koonrungsesomboon et al, 2018 Pharmacogenomics J. 18(6):760-768 / Thorn et al., 2012, Pharmacogenet Genomicsm 22(1): 73-77 / Zhou et al. 2010, Drug Met Rev 42:268 / Ghotbi et al. 2007, Eur J Clin Pharmacol 63:537
