Editing CYP3A4 (section)

== Mechanisms ==
[[Cytochrome P450]] enzymes perform an assortment of modifications on a variety of [[ligand]]s, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds. These include [[hydroxylation]], [[epoxide|epoxidation]] of [[olefins]], aromatic [[redox|oxidation]], heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, [[dehydrogenation]] reactions, and aromatase activity.<ref name="pmid9351897">{{cite journal | vauthors = Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, Watkins PB | title = Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins | journal = Drug Metabolism and Disposition | volume = 25 | issue = 11 | pages = 1228–33 | date = November 1997 | pmid = 9351897 }}</ref><ref name="Shahrokh_2012">{{cite journal | vauthors = Shahrokh K, Cheatham TE, Yost GS | title = Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1820 | issue = 10 | pages = 1605–17 | date = October 2012 | pmid = 22677141 | pmc = 3404218 | doi = 10.1016/j.bbagen.2012.05.011 }}</ref>

Hydroxylation of an [[sp3 bond|sp<sup>3</sup>]] [[C-H bond]] is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.<ref name="Meunier_2004">{{cite journal | vauthors = Meunier B, de Visser SP, Shaik S | s2cid = 33927145 | title = Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes | journal = Chemical Reviews | volume = 104 | issue = 9 | pages = 3947–80 | date = September 2004 | pmid = 15352783 | doi = 10.1021/cr020443g }}</ref> In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.<ref name="Shahrokh_2012" /> An example of a molecule that undergoes more than one reaction due to CYP3A4 includes [[tamoxifen]], which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.<ref name="Shahrokh_2012" />

Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes. [[File:Hydroxylation Mechanisms of Cytochrome P450 Enzymes.png|thumb|Two of the most commonly proposed mechanisms used for the hydroxylation of an sp<sup>3</sup> C–H bond]] The first pathway suggested is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a "[[radical clock]]".<ref name="Meunier_2004" />