Generalized cytochrome P450-mediated oxidation and oxygenation reactions in aromatic substrates with activated N-H, O-H, C-H, or S-H substituents

Koymans, Luc; Kelder, Gabriëlle M. Donné-Op den; Koppele, J.M. te; Vermeulen, Nico

doi:10.3109/00498259309059401

Cited by 21 publications

(10 citation statements)

References 35 publications

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“…is presented in Fig. 8(a) 62. The formation of the radical intermediate is believed to occur via electron transfer followed by proton abstraction.…”

Section: Resultsmentioning

confidence: 99%

Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions

Jurva

Wikström

Weidolf

et al. 2003

Rapid Comm Mass Spectrometry

191

197

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The extent to which electrochemistry on-line with electrospray mass spectrometry can be used to mimic cytochrome P450 catalyzed oxidations has been investigated. Comparisons on the mechanistic level have been made for most reactions in an effort to explain why certain reactions can, and some cannot, be mimicked by electrochemical oxidations. The EC/MS/MS system used successfully mimics in cases where the P450 catalyzed reactions are supposed to proceed via a mechanism initiated by a one-electron oxidation, such as N-dealkylation, S-oxidation, P-oxidation, alcohol oxidation and dehydrogenation. The P450 catalyzed reactions initiated via direct hydrogen atom abstraction, such as O-dealkylation and hydroxylation of unsubstituted aromatic rings, generally had a too high oxidation potential to be electrochemically oxidized below the oxidation potential limit of water, and were not mimicked by the EC/MS/MS system. Even though the EC/MS/MS system is not able to mimic all oxidations performed by cytochrome P450, valuable information can be obtained concerning the sensitivity of the substrate towards oxidation and in which position of the molecule oxidations are likely to take place. For small-scale electrochemical synthesis of metabolites, starting from the drug, the EC/MS/MS system should be very useful for quick optimization of the electrochemical conditions. The simplicity of the system, and the ease and speed with which it can be applied to a large number of compounds, make it a useful tool in drug metabolism research.

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“…is presented in Fig. 8(a) 62. The formation of the radical intermediate is believed to occur via electron transfer followed by proton abstraction.…”

Section: Resultsmentioning

confidence: 99%

Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions

Jurva

Wikström

Weidolf

et al. 2003

Rapid Comm Mass Spectrometry

191

197

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“…abstraction from NH to form an N-centered radical, followed by radical combination with HO . (i.e., an O-atom rebound) [162]. The formation of N-hydroxyamides is documented for a number of compounds, in particular carcinogenic N-arylamides [4] [163].…”

Section: Fig 253mentioning

confidence: 99%

The Biochemistry of Drug Metabolism — An Introduction. Part 2. Redox Reactions and Their Enzymes

Testa

Kraemer

2007

ChemInform

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This Part 2 of our biochemical introduction to drug metabolism [1] presents the redox reactions (oxidations and reductions) and their enzymes. As stated in Part 1, these reactions are clearly the most important ones in drug and xenobiotic metabolism. There are at least three reasons for this state of affairs. First, the biotransformation of a xenobiotic often begins with redox reactions, and particularly reactions catalyzed by cytochromes P450 (abbreviated as CYPs). Second, a vast majority of drugs (and of other xenobiotics, as far as this information is available) are substrates of CYPs [2 -10]. Although any attempt to quantify the total number of marketed drugs, drug candidates, and preclinical candidates that are substrates of human CYPs is but a guess-estimate, a figure of ca. 90% is generally accepted. This percentage is certainly higher when all drug-metabolizing oxidoreductases are taken into account.The third reason for the predominance of redox reactions in drug metabolism is the large diversity of metabolites that may be produced from a single substrate. This diversity involves differences in the chemical nature of the resulting functional groups (chemoselectivity, e.g., a phenolic OH vs. an N-oxido group), as well as positional or stereochemical differences in the creation of a single type of functional group (regioselectivity, e.g., an ortho-vs. a para-phenolic OH, or stereoselectivity, e.g., a cis-vs. trans-alcoholic OH; see Fig. 1.15 in Part 1 [1]). As a first glance of what will be summarized in Part 2, we note here that the metabolites resulting from redox reactions are alcohols, phenols, aldehydes, ketones, carboxylic acids, primary and secondary amines, hydroxylamines, N-oxides, sulfides, sulfoxides or sulfones, to name the major ones. Many of these types of metabolites can be produced by CYP-catalyzed oxidations or reductions. None the less, the contribution of other oxidoreductases should not be underestimated.Some of the reactions catalyzed by CYPs are also carried out (often in parallel on the same substrate) by the flavin-containing monooxygenases (FMOs), another important class of xenobiotic-metabolizing enzymes which will be presented in parallel with the CYPs. Indeed and as we shall see, numerous further oxidoreductases are involved in drug and xenobiotic metabolism [4] [7] [9]. Like CYPs, they can act directly on a foreign substrate or on a metabolite thereof, but none of these oxidoreductases metabolizes as many substrates as CYPs. Still, some of these enzyme systems metabolize a marked number of compounds (e.g., alcohol dehydrogenases) and are

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“…The direct insertion of oxygen into the carbon-hydrogen bond at the site of hydroxylation has also been entertained as a more common mechanism of hydroxylation of aromatic systems (Figure 1, pathway B) (13). More recently, P450 catalysis has been postulated to involve an initial abstraction of a hydrogen atom from the hydroxyl group of the phenol and subsequent electron spin delocalization to a carboncentered radical ortho to the phenolic substituent (14,15). Recombination of this postulated radical intermediate with a hydroxyl radical has been thought to result in catechol product formation (Figure 1, pathway C).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Cytochrome P450-Catalyzed Aromatic Hydroxylation of Estrogens

Sarabia

Zhu

Kurosawa

et al. 1997

Chem. Res. Toxicol.

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The mechanism of aromatic hydroxylation of estrogens by cytochrome P450 enzymes has been examined by comparing the oxidation of estrone with that of substrates carrying additional aromaticity such as equilenin and the structural analog 2-naphthol. Hamster liver microsomes preferentially catalyzed the conversion of estrone to 2-hydroxyestrone (Km = 30 and 25 microM and Vmax = 1497 and 900 pmol (mg of protein)-1 min-1 for 2- and 4-hydroxyestrone formation, respectively). In contrast, equilenin was hydroxylated exclusively at C-4 of the steroid ring system and 2-naphthol at the corresponding C-1 position (Km = 67 and 42 microM and Vmax = 2083 and 3226 pmol (mg of protein)-1 min-1 for 4-hydroxyequilenin and 1,2-dihydroxynaphthalene formation, respectively). This shift in the specificity of hydroxylation was due to the introduction of additional aromaticity at ring B of equilenin, because hamster liver microsomes are known not to contain any estrogen-4-hydroxylase, only estrogen-2-hydroxylase activity catalyzed by cytochrome P450 3A family enzymes. The exclusive 4-hydroxylation of equilenin is proposed to be due to a preferred delocalization of the naphthoxy radical an intermediate in the hydroxylation, to C-4, whereas delocalization to C-2 requires additional activation energy and is energetically not favored. Based on these electronic considerations, a mechanism of aromatic hydroxylation of estrogens is proposed which features hydrogen abstraction from the phenolic hydroxy group, electron delocalization of the phenoxy radical to a carbon-centered radical, and subsequent formation of catechol metabolites by hydroxy radical addition at C-2 or C-4 depending on steric or electronic constraints.

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Generalized cytochrome P450-mediated oxidation and oxygenation reactions in aromatic substrates with activated N-H, O-H, C-H, or S-H substituents

Cited by 21 publications

References 35 publications

Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions

Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions

The Biochemistry of Drug Metabolism — An Introduction. Part 2. Redox Reactions and Their Enzymes

Mechanism of Cytochrome P450-Catalyzed Aromatic Hydroxylation of Estrogens

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