Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Abstract

This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, "general chemicals," natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10-15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.

Keywords: Bioactivation; Flavin-containing monooxygenase; Molybdenum hydroxylases; Monoamine oxidase; NAD(P)H quinone oxidoreductase; Natural products; Xenobiotics.

Fig. 1

Human FMO enzymes participating in the metabolism of drugs (data calculated for major and minor enzymes from Table 3; a total of 114 drugs used in calculations)

Fig. 2

General reaction of N-oxygenation of primary amines by FMO

Fig. 3

Typical oxygenation reaction catalyzed by FMO enzymes, where R denotes part of the molecule and X is a heteroatom, usually N or S

Fig. 4

Oxygenation of substrates with FMO enzymes

Fig. 5

Baeyer–Villiger oxidation of cyclohexanone by the flavoprotein monooxygenase FMO5 (Guengerich and Yoshimoto 2018). Some uncoupling also occurs to generate H₂O₂ (Fiorentini et al. ; Walsh 1979)

Fig. 6

Some Baeyer–Villiger C–C oxidations of drugs catalyzed by FMO (Guengerich and Yoshimoto 2018)

Fig. 7

Clozapine metabolism by human FMO and P450 enzymes (Fang et al. ; Tugnait et al. 1999, 1997)

Fig. 8

Oxygenation of nicotine by FMO enzymes

Fig. 9

Oxygenation of cimetidine by FMO enzymes

Fig. 10

Oxygenation of ranitidine by FMO enzymes

Fig. 11

Chlorpromazine oxygenations by FMO and P450 enzymes

Fig. 12

N-Oxygenation of dimethylamphetamine

Fig. 13

N-Oxygenation of trimethylamine by FMO3

Fig. 14

N-Oxygenation of amphetamine

Fig. 15

N-Oxygenation of N-methylamphetamine

Fig. 16

N-Oxygenation of arecoline by FMO enzymes

Fig. 17

Oxygenation of thiourea by FMO enzymes

Fig. 18

Oxygenation of fenthion by FMO enzymes

Fig. 19

Typical reaction catalyzed by MAO enzymes, where R denotes part of the molecule

Fig. 20

Substrate oxidation by MAO enzymes (Edmondson et al. 2007)

Fig. 21

Deamination of benzylamines by MAO enzymes

Fig. 22

Ozanimod metabolism by P450 and MAO enzymes

Fig. 23

Phenelzine oxidation to β-phenylethylidenehydrazine

Fig. 24

Deamination of tyramine by MAO enzymes

Fig. 25

Activation and deactivation of dopamine

Fig. 26

Bioactivation and detoxication of MPTP by MAO and P450 enzymes

Fig. 27

Typical reaction catalyzed by NQO enzymes

Fig. 28

General reaction catalyzed by molybdenum hydroxylases

Fig. 29

Catalytic cycle and proposed mechanism for the oxidation of aromatic heterocycles and aldehydes by the molybdenum hydroxylases using quinazoline as an example (glutamate numbering represents human AOX) (Alfaro and Jones 2008)

Fig. 30

General reaction of nitrite reduction catalyzed by molybdenum hydroxylases

Fig. 31

Proposed mechanism for reduction of nitrite to nitric oxide in the presence of a reducing substrate by the molybdenum hydroxylases (Maia and Moura 2018)

Fig. 32

Typical reaction catalyzed by AOX and XO enzymes

Fig. 33

Oxidation of phthalazine by AOX

Fig. 34

Oxidation of DACA by AOX

Fig. 35

Bioactivation of lapatinib by P450 3A enzymes and oxidation by AOX

Fig. 36

Oxidation and N-deethylation of zaleplon by AOX and P450 3A enzymes

Fig. 37

Oxidation of idelalisib by AOX and P450 3A enzymes

Fig. 38

Oxidation of retinaldehyde to retinoic acid by AOX

Fig. 39

Oxidation of citalopram by P450, MAO, and AOX enzymes to citalopram propionic acid

Fig. 40

Oxidation of KW-2449 to an oxo-piperazine metabolite by MAO B and AOX

Fig. 41

N-Oxidation of oxycodone by FMO and retro-reduction by AOX and other enzymes

Fig. 42

S-Oxidation of sulindac by FMO and sulfoxide reduction by AOX

Fig. 43

Benzisothiazole reduction and thiol methylation of ziprasidone by AOX and thiol methyltransferase

Fig. 44

Nitro reduction and N-acetylation of nitrazepam by AOX and NAT

Fig. 45

Nitro reduction and N-acetylation of dantrolene by AOX and NAT

Fig. 46

Oxidation of SGX-523 to a poorly soluble lactam metabolite by AOX

Fig. 47

Oxidation of methotrexate to a poorly soluble lactam metabolite by AOX

Fig. 48

Hydrolysis of GDC-0834 to an aniline metabolite by AOX

Fig. 49

Proposed mechanism of hydrolysis of GDC-0834 by AOX

Fig. 50

Oxygenation of purine compounds by XOR enzymes

Fig. 51

Oxidation of hypoxanthine to xanthine and uric acid by XOR

Fig. 52

Oxidation of allopurinol to oxypurinol by AOX and XOR enzymes

Fig. 53

Oxidation of 6-deoxyacyclovir to the active metabolite acyclovir by XOR

Fig. 54

Oxidation of 6-mercaptopurine to 6-thiouric acid by AOX, XO, and XDH

Fig. 55

Metabolism of pyrazinamide to active and toxic metabolites via amidase and XOR catalyzed reactions