Abstract
Data are presented on the formation of potentially toxic metabolites of drugs that are substrates of human drug metabolizing enzymes. The tabular data lists the formation of potentially toxic/reactive products. The data were obtained from in vitro experiments and showed that the oxidative reactions predominate (with 96% of the total potential toxication reactions). Reductive reactions (e.g., reduction of nitro to amino group and reductive dehalogenation) participate to the extent of 4%. Of the enzymes, cytochrome P450 (P450, CYP) enzymes catalyzed 72% of the reactions, myeloperoxidase (MPO) 7%, flavin-containing monooxygenase (FMO) 3%, aldehyde oxidase (AOX) 4%, sulfotransferase (SULT) 5%, and a group of minor participating enzymes to the extent of 9%. Within the P450 Superfamily, P450 Subfamily 3A (P450 3A4 and 3A5) participates to the extent of 27% and the Subfamily 2C (P450 2C9 and P450 2C19) to the extent of 16%, together catalyzing 43% of the reactions, followed by P450 Subfamily 1A (P450 1A1 and P450 1A2) with 15%. The P450 2D6 enzyme participated in an extent of 8%, P450 2E1 in 10%, and P450 2B6 in 6% of the reactions. All other enzymes participate to the extent of 14%. The data show that, of the human enzymes analyzed, P450 enzymes were dominant in catalyzing potential toxication reactions of drugs and their metabolites, with the major role assigned to the P450 Subfamily 3A and significant participation of the P450 Subfamilies 2C and 1A, plus the 2D6, 2E1 and 2B6 enzymes contributing. Selected examples of drugs that are activated or proposed to form toxic species are discussed.
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Introduction
A previous analysis of the published data on the participation of human oxidoreductase enzymes in the general metabolism of drugs showed that cytochrome P450 (P450, CYP) enzymes participate to the greatest extent, to the extent of 96% (Rendic and Guengerich 2015). The participation of other enzymes was: aldo–keto reductase (AKR) 1%, monoamine oxidase (MAO) 1%, flavin-containing monooxygenase (FMO) 2%, and the group of minor participating enzymes < 1%. Within the P450 Superfamily, the participation in the general metabolism of drugs (considering both drugs under development and marketed drugs) was: Subfamily 3A-33%, followed by the Subfamily 2C-24%, the Subfamily 1A-14%, and P450 2D6-13%. An estimate of the participation of P450 subfamilies in the number of reactions, taking into account just the metabolism of marketed drugs, was: Subfamily 3A-28%, Subfamily 2C-25%, Subfamily 1A-12%, and the 2D6 enzyme-13%. The contribution of other P450 enzymes ranged from 1 to 5% in both cases (data for the analysis collected up to 2015 (Rendic and Guengerich 2015). Thus, in addition to the P450 Subfamily 3A, a relatively large contribution to the general drug metabolism was shown for Subfamilies 2C and 1A and the P450 2D6 enzyme. The results of the analysis also showed that the main five P450 enzymes that catalyze the metabolism of marketed drugs are P450 3A4- 22%, 2D6 -14%, 2C19-9%, 2C9- 10%, and 1A2-8%, accounting for 63% of the marketed drug P450 metabolism reactions in humans (Rendic and Guengerich 2015). However, an analysis of recently approved drugs (2015–2020) showed that P450s are involved in 80% of the metabolism of these drugs and P450 3A4/3A5 in 52% (Bhutani et al. 2021). Another analysis of the reactions of drugs resulting in the formation of potentially toxic metabolites or intermediates (toxication reactions) as substrates of the P450 Families 1- 4 showed that 6% of the reactions involved reported toxication reactions (Rendic and Guengerich 2021). Of the 4039 reactions, 235 (6%) involve the formation of potentially toxic intermediates or metabolites. Clear domination of P450 3A4 in the catalysis of toxications compared with other P450s was also shown in this case, catalyzing 25% of the reactions (Rendic and Guengerich 2021).
The present report updates the data on the metabolism of drugs to potentially toxic/reactive products (toxication reactions) by human drug enzymes, including additional enzymes along with the well-studied P450 enzymes. The data on 40 enzymes (20 P450 and 20 other enzymes) that catalyze oxidative, reductive, hydrolysis, and/or conjugation reactions of drugs resulting in the formation of potentially toxic metabolites or intermediates are included in the analysis (Table 1). The results of the analysis are summarized in a total of 327 records organized in alphabetical order for an easier approach and are tabularly presented (Table 2 (drugs A-D), Table 3 (drugs E-J), and Table 4 (drugs J-Z). In the analysis included are also reactions and products that are not toxic but as substrates but in additional reactions products or intermediates formed exert toxic effects (e.g. products of hydroxylation reactions catalyzed by P450 enzymes and products of hydrolysis reactions).
Explanations of abbreviations of the enzyme names are presented in Table 1. Data presented in Table 2, 3, and 4 are used for calculations presented in Figs. 1 and 2. Minor enzymes were designated as those that participate with less than 10% of the data presented in Table 2, 3, and 4.
Participation of human metabolizing enzymes in the toxication of drugs (data calculated on 79 drugs and 21 metabolites)
Participation of human P450 enzymes in the toxication of drugs and products (data calculated on 79 drugs and 21 metabolites)
Results and discussion
The present report presents data on the activation of drugs to potentially toxic or reactive products catalyzed by human drug-metabolizing enzymes (Table 1). The data, including reactions resulting in the formation of reactive/toxic products formed on the activation of drugs and metabolites, are presented in Table 2, 3, and 4. The reactions presented are catalyzed by 40 human enzymes and include oxidative reactions (e.g., C-, N-, and S-oxidation, epoxide formation, dechloroethylation, O- and N-demethylation, and desulfuration). The data presented were obtained from in vitro experiments and showed that the oxidative reactions (e.g., C-, N-, and S-oxidation, epoxide formation, dechloroethylation, O- and N-demethylation, and desulfuration) predominate (with 96% of the total potential toxication reactions). Reductive reactions (e.g., reduction of nitro to amino group and reductive dehalogenation) participate to the extent of 4%. (Fig. 1).
The calculated participation of human metabolizing enzymes (Fig. 1, Table 1) in the toxication of drugs and their products shows the dominant role of P450 enzymes (72%), followed by MPO (7%), FMO (3%), AOX, (4%), SULT (5%), and a group of other enzymes (AADAC, ADH, CAT, CES, COX, CPR and POR, LPO, HB + H2O2, NR, NAT, MAO, XOR), which participate to the extent of 9%. In our previous analysis, the participation of human P450 enzymes in the general oxidative and reductive metabolism of drugs was calculated to be ~ 96% (Rendic and Guengerich 2015). The results of the present analysis, which takes into account only toxication reactions and includes additional enzymes (e.g., MPO, AOX, FMOs, and SULT), show a lower participation of P450 enzymes in the bioactivation of drugs to toxic products compared to the general metabolism of drugs.
The previous analysis of the bioactivation of drugs to toxic products within the Family 1–4 P450 enzymes showed that the P450 3A4 enzyme dominates by catalyzing ~ 25% of the reactions (Rendic and Guengerich 2021). Domination of the P450 Subfamily 3A and 2C enzymes was also shown in the present analysis, as the members of P450 Subfamily 3A (P450 3A4 and P450 3A5) participated in the bioactivation of drugs and products to an extent of 27% and the members of Subfamily 2C (P450 2C9, P450 2C19) to an extent of 16%. Other enzymes participated in the bioactivation reactions to the following extents P450 1A1 5%, P450 2D6 8%, P450 2E1 10%, and P450 2B6 6%. All other P450 enzymes (minor enzymes) (P450 1B1, 2C8, 2C18, 2C9.1, 2C9.2, 2C9.3, 2J2, 2A6, 2J2, and 4A11) participated to the extent of 14% (Fig. 2). For comparison, previous analyses of the participation of the human P450 families of enzymes in the general metabolism of drugs also showed the dominance of the P450 Subfamily 3A with 33%, that of the P450 Subfamily 2C with 24%, and that of the P450 2D6 and 1A2 enzymes at 13% and 14%, respectively (Rendic and Guengerich 2015). Thus, the results of the present analysis correspond to the data presented previously, but with a slightly lower participation of the P450 enzymes in the bioactivation of drugs to toxic products compared to the results of the participation of the enzymes in the general metabolism of the drugs. In both cases, however, the dominance of the Subfamily P450 3A and Subfamily 2C enzyme was shown.
The data show that some of the drugs were removed from the market because of toxic effects (e.g., amphetamine, danthron, ellipticine, enflurane, nomifensine, thalidomide, thioridazine, troglitazone, zomepirac, phenacetin, flunitrazepam, tolcapone). Some of these discontinued drugs returned to the market for applications under controlled conditions and for specific illnesses (e.g., thalidomide, amphetamine, ellipticine). The drugs are substrates in either oxidative or reductive metabolic reactions catalyzed by one or several enzymes, in which the formation of various reactive products is achieved by toxication reactions (Table 2, 3, and 4). Some reactive species formed in the course of drug metabolism may be deactivated in reactions with reduced glutathione (GSH).
Depending on the structural properties and enzymes involved, the drugs participate predominantly as substrates in oxidative reactions involving C, N, and S atoms. Reductive reactions are minor in the toxication of the drugs, e.g. reduction of nitro to amino groups (e.g., chloramphenicol, clonazepam, flunitrazepam, and flutamide). For example, toxication by reduction or oxidation of chloramphenicol and its metabolites is shown in Fig. 3. The reactions involve the reduction of the nitro to nitroso and N-hydroxy groups, oxidations with the formation of nitroxide radicals and reactive oxygen species, and consequent DNA damage. Additional reactions are the formation of a reactive acyl chloride from chloramphenicol as a P450 oxidation product, shown in rat liver microsomes. This reaction leads to the formation of additional reactive metabolite(s) that inhibit reaction(s) catalyzed by P450 enzymes, as reported in rats. This reaction might result in drug-drug interaction when chloramphenicol is coadministered with other drugs that are metabolized by the P450 enzymes, e.g. voriconazole (Fig. 3, Table 2 and references therein).
Metabolic reactions and toxication of chloramphenicol and metabolites
Drug bioactivation reactions usually comprise a set of reactions in which products may be toxic to cells. The structures representing some proposed or suggested activated products that might be formed during drug metabolism are shown in Fig. 4A, B, with examples of enzymes and drug substrates.
A, B Examples of reactive and toxic products formed by metabolism of drugs
When a drug, in the course of its metabolism, forms reactive species, there might be a risk of toxic reactions. The reactions may be identified either in vitro or in vivo in the course of drug development (Fig. 4a, b). For instance, both reductive and oxidative dehalogenation reactions of halothane have led to the formation of reactive species (the formation of radicals) and toxic reactions (e.g., liver necrosis and cytotoxicity). The toxic reactions led to the withdrawal of the drug from use as an inhalation anesthetic drug in some countries (Rendic and Guengerich 2021). For enflurane, tolcapone, ellipticine derivatives, and troglitazone, reactive species are formed by oxidative reactions, including N-oxidation, C-hydroxylation, and dehydrogenation (Table 2, 3, and 4, and the references therein). The products of drugs formed by the reactions catalyzed by P450 enzymes might be activated either by additional oxidation or as conjugation. An example is the antiestrogen drug tamoxifen and its metabolite 3-hydroxytamoxifen (Droloxifen®), which is also utilized as a drug. 3-Hydroxytamoxifen is reported to be bioactivated by O-sulfation to form the therapeutically active form of the drug. However, catechols formed by C-3 and C4-hydroxylation, after oxidation to o-quinones, may covalently bind to cellular macromolecules. Hydroxylation at C-3 and consequent sulfate conjugation are considered detoxication reactions that result in the formation of therapeutically active drugs. However, α-hydroxylation and consequent sulfate conjugation are considered toxication reactions (Kim et al. 2005). Thus, bioactivation of hydroxylated products to toxic metabolites results from their oxidations to quinone(s), semiquinone(s), and epoxides at olefins and phenyl rings. Examples of the reactive species formed and the reactions of activation of tamoxifen into reactive (toxic) metabolites are presented in Figs. 4A, B, 5, and Table 4 and references therein.
Metabolic reactions and toxication of tamoxifen and metabolites
The structurally related antiestrogenic drug toremifene can be metabolized as a substrate of P450 enzymes with the formation of an N-desmethyl product and an epoxide or by the formation of 4-hydroxy and toremifene α-hydroxy metabolites. Hydroxy metabolites of tormifene exert low toxic properties due to limited O-sulfation by hydroxysteroid sulfotransferases, resulting in limited formation of DNA adducts (Fig. 6, Table 4, and references therein).
Metabolic reactions and toxication of toremifene and metabolites
Nimesulide is a nonsteroidal anti-inflammatory drug associated with hepatotoxicity. It was suggested that hepatotoxicity of nimesulide results from the oxidation of the product 4-amino-2-phenoxy-methanesulfonamide to a toxic diiminoquinone, catalyzed by P450 and MPO enzymes (Fig. 4A, Table 4, and references therein).
It has been reported that MPO, in the presence of H2O2 or HOCl, activates various drugs or their products. Examples include carbamazepine, diclofenac, indomethacin, fluperlapine, phenytoin, and thiabendazole metabolites. The products of MPO oxidation are either stable or reactive metabolites. The reactive products include free radicals, reactive oxygen species, quinones, and iminoquinone species (Tables 2, 3, and 4 and references therein, and Fig. 4a, b).
Carbamazepine is metabolized to toxic species by multiple reactions catalyzed by P450s and the enzyme MPO. P450-catalyzed reactions include the formation of a C10,11 epoxide (P450 3A4 as the major enzyme), hydroxylation at C2 and C3 (as major metabolites), and the formation of an iminoquinone and o-quinone. The formation of a toxic C10,11 epoxide is catalyzed by multiple P450 enzymes but is a minor reaction in the overall metabolism of carbamazepine. MPO, in the presence of H2O2, catalyzes the oxidation of the C2- and C3-hydroxy products of carbamazepine with the formation of free radicals and reactive oxygen species (Table 2 and references therein, and Figs. 4A, B and 7).
Metabolic reactions and toxication of carbamazepine and metabolites
A major reaction of diclofenac metabolism is the C-4´ hydroxylation catalyzed by P450s, with P450 2C9 as the major enzyme. Other hydroxylated metabolites (C5-hydroxy, C4´,5-dihydroxy, and C3-hydroxy) account for < 10% of the products. Toxication of diclofenac, resulting in the formation of protein adducts, is linked to its oxidative metabolism and hydroxylated metabolites formed by P450 enzymes. The proposed toxic products are 1´,4´, and 2,5-quinoneimines, o-imine methide, and an arene oxide. MPO, in the presence of H2O2 or neutrophils, oxidizes diclofenac and 5-hydroxy diclofenac to a toxic quinoneimine (Table 2 and references therein, Figs. 4a and 8).
Metabolic reactions and toxication of diclofenac and metabolites
In the case of thalidomide, which was withdrawn from the market because of its teratogenicity, proposed toxic metabolites are formed by P450-catalyzed reactions (e.g., hydroxylations, epoxidation, oxidation to quinones, and formation of reactive oxygen species). The reactions are catalyzed by P450s (with P450 3A4 and 2C19 as the major enzymes), and NR enzymes (Figs. 4a, b, 9, Table 4 and references therein). The toxic species thus formed (epoxides and quinones) might be detoxicated by reaction with reduced GSH or may exert toxicity by reacting with cell macromolecules (e.g., proteins and DNA) (Chowdhury et al. 2010; Wani et al. 2017) (Fig. 9 and Table 4 and references therein).
Metabolic reactions and toxication of thalidomide and metabolites
< insert Fig. 9 here >
Referring to the data presented in Tables 2, 3, and 4, and Fig. 4A, B it has to be considered that when characterizing the candidate drug as potentially toxic or non-toxic there is a close relationship between the structure of a drug and the activity of enzymes present in the cells of the targeted tissue. The results presented in this report have been obtained in vitro, but the side/toxic effects have been clinically noted resulting in some cases the removal of the drug from the market (e.g. thalidomide and other drugs, Tables 2, 3, and 4). The final effect of the drug in vivo might be, influenced by polymorphism and/or inhibition/induction of the activity of the major enzyme whose activity is related to the toxic effect(s), which may significantly affect the formation of toxic products. For instance, a reaction that is characterized by a high Km value, or an enzyme characterized as a “minor enzyme„ may become dominant if the reaction/enzyme characterized by low Km values or when the “major “ enzyme is inhibited by drug overdose or other concomitantly administered drug/chemical/food, or if the active form of the enzyme is not present in the cell due to genetic polymorphism. Considering the structural characteristics of the candidate drug with the possibility to form potentially toxic metabolites/intermediates as obtained in vitro might lower the incidence of consequent more or less serious side effects to the patients in vivo and even affect the rate of drug application-related deaths (European Drug Report 2023).
Concluding remarks
In the present report, the in vitro data on the toxication of drugs were updated, and additional enzymes (e.g., SULT, AOX, MPO, and some minor participating enzymes) were included in the analysis. The present data show the continued predominant participation of P450 enzymes in the both metabolism and toxication of drugs, probably due to extensive research on this superfamily of enzymes during the last 30 years. P450 enzymes catalyze 78% of toxication reactions. The dominant enzymes catalyzing toxication reactions of drugs belong to the P450 Subfamily 3A, catalyzing 28% of the reactions. Significant participation of the P450 Subfamilies 2C and 1A and P450 2D6 enzyme was also noted at this time in the toxication of drugs and metabolites. The results of the present analysis confirm the previous finding that human P450 enzymes still predominate in the metabolic toxication of the drugs catalyzing the formation of reactive/toxic products, but more additional enzymes have been identified to catalyze the toxication of drugs. Research on the toxication of drugs should include other enzymes catalyzing oxidative/reductive reactions and performing candidate drug toxicity/risk management to prevent serious side effects, withdrawal of the candidate drug from the market, and even drug-related deaths.
Availability of data and materials
All data are available in the text and tables of the review.
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The authors thank Jan Dragašević for assistance in the preparation of the manuscript.
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One of the authors (F. P. G.) was supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) grant number R01 GM118122 [to F. P. G.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Rendic, S.P., Guengerich, F.P. Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes. Arch Toxicol 98, 1581–1628 (2024). https://doi.org/10.1007/s00204-024-03710-9
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DOI: https://doi.org/10.1007/s00204-024-03710-9