P450-catalyzed aromatic hydroxylation

A relatively stable QM is produced by initial P450-catalyzed aromatic hydroxylation of the SERM tamoxifen to yield 4-hydroxytamoxifen, followed by a cytochrome P450-catalyzed direct two-electron oxidation (Scheme 10.9).7 58 This QM is extremely long lived at physiological pH and temperature (tl/2 3 h, Table 10.2),59 most likely... 

That cytochrome P450-catalyzed aromatic hydroxylation proceeded by a mechanistic pathway that was generally consistent with the rules of electrophilic aromatic substitution was never in doubt because of the abundance of experimental evidence supporting this conclusion. Despite the certainty of product formation, establishing the exact mechanism that defines the pathway has proved to be difficult. 

Mechanism of cytochrome P450-catalyzed aromatic hydroxylation of estrogens. Chem. Res. Toxicol., 10, 767-771. 

Sarabia, S.F., B.T. Zhu, T. Kurosawa, M. Tohma, and J.G. Liehr (1997). Mechanism of cytochrome P450-catalyzed aromatic hydroxylation of estrogens. Chem. Res. Toxicol. 10, 767-771. 

Darbyshire JF, Iyer KR, Grogan J, et al. Substrate probe for the mechanism of aromatic hydroxylation catalyzed by cytochrome P450. Drug Metab Dispos 1996 24(9) 1038-1045. 

Cytochromes P450 catalyze oxidative and reductive reactions. Oxidative biotrasfor-mations are more frequent and include aromatic and sidechain hydroxylation, N-, 0-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation and desulfuration. The majority of these reactions require the formation of radical species this is usually the rate-determining step for the reactivity process [24],... 

Scheme 1 Typical reactions catalyzed by cytochromes P450 (a) hydroxylation of saturated hydrocarbons (b) heteroatom oxidation and dealkylation (c) olefin epoxidation (d) aromatic hydroxylation (e) desaturation (f) aldehyde deformylation.

Some of the important reactions catalyzed by the P450 monooxygenase system include aliphatic hydroxylation, aromatic hydroxylation, epoxidation, heteroatom (N-, 0-, and S-)dealkylation, nitrogen oxidation, oxidative deamination, oxidative dehalo-genation, oxidative denitrification, and oxidative desulfuration. Most of these reactions result from the initial oxidation of a carbon atom, another reason that P450 is so important in the oxidative biotrans-formation of lipophilic chemicals. Some P450-cataly-zed oxidation reactions are illustrated in Table 2. 

Among the reactions catalyzed by cytochrome P450 are (a) aliphatic oxidation, (b) aromatic hydroxylation, (c) N-hydroxylation, (d) N-dealkylation, and (e) O-dealkylation. 

Koerts, J., M.M.C. Velraeds, A.E.M.F. Sofferse, J. Vervoort, and I.M.C.M. Rietjens (1997). Influence of substituents in fluorobenzene derivatives on the cytochrome P450-catalyzed hydroxylation at the adjacent ortho aromatic carbon center. Chem. Res. Toxicol. 10, 279-288. 

Koerts J, Soffers AEMF, Vervoort J, De Jager A, Rietjens IMCM (1998) Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. Chem Res Toxicol 11 503-512... 

P450 2D6 catalyzes maity of the basic kinds of oxidative reactions of P450s, e.g., aliphatic and aromatic hydroxylations, heteroatom dealkylations, etc. [887]. In early work in this laboratory [888], the observation was made that many of the substrates contained a basic nitiDgen atom situated 5 A away from the site of oxidation, possibly due to a specific anionic charge in P450 2D6. Subsequently more detailed pharmacophore models have been developed [889-892]. All of these are based on the premise that a basic nitrogen atom in the molecule interacts (coulom-bic bond) with an acidic anuno acid in P450 2D6, usually Asp-301 in most studies. (More recent work shows a role for Glu-216, however, vide infra.)... 

Aromatic hydroxylation also belongs to the common P450 reactions. P450NikF from Streptomyces tendae Tii901 has been claimed to catalyze hydroxylation of pyridylhomothreonine (14) to form hydroxypyridylhomothreonine (15) in the biosynthesis of nikkomydn, an inhibitor of diitin synthase [61] (Scheme 12.4). Many P450s have been engineered toward aromatic hydroxylation, since this ability makes them attractive candidates for the production of fine chemicals (see Sections 12.4 and 12.5.3). 

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