Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes

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.

Keywords: Drugs; Human enzymes; Reactive species; Toxic metabolites; Toxicity impact.

Fig. 1

Participation of human metabolizing enzymes in the toxication of drugs (data calculated on 79 drugs and 21 metabolites)

Fig. 2

Participation of human P450 enzymes in the toxication of drugs and products (data calculated on 79 drugs and 21 metabolites)

Fig. 3

Metabolic reactions and toxication of chloramphenicol and metabolites

Fig. 4a and 4b

Examples of reactive and toxic products formed by metabolism of drugs

Fig. 4a and 4b

Examples of reactive and toxic products formed by metabolism of drugs

Fig. 5

Metabolic toxication of tamoxifen and metabolites

Fig. 6

Metabolic reactions and toxication of toremifene and metabolites

Fig. 7

Metabolic reactions and toxication of carbamazepine and metabolites

Fig. 8

Metabolic reactions and toxication of diclofenac and metabolites

Fig. 9

Metabolic reactions and toxication of thalidomide and metabolites