Aman Edited by Margaret Hilton Honors Organic Chemistry Chem 2321 Sigman 2013 Cytochrome P450 Oxidase Overview Cytochrome P450 Oxidases CYPs are the principal enzymes implicated in drug metabolism catalyzing approximately 75 of reactions 1 The ID: 1038835
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1. Cytochrome P450 OxidaseCreated by Joseph AmanEdited by Margaret HiltonHonors Organic ChemistryChem 2321 (Sigman), 2013
2. Cytochrome P450 OxidaseOverview: Cytochrome P450 Oxidases (CYPs) are the principal enzymes implicated in drug metabolism, catalyzing approximately 75% of reactions (1). The heme iron reacts with molecular oxygen and NADPH to produce a highly reactive intermediate called compound I.CYP Wiki Page: http://en.wikipedia.org/wiki/Cytochrome_P450 Drug Metabolism: http://en.wikipedia.org/wiki/Drug_metabolismOther References: 1. Guengerich, et. al. Chem. Res. Toxicol, 2008, 21 (1), pp 70–83 2. Axelrod, et. al, Journal of Pharmacology, 1955, vol. 114 no. 4, pp. 430-438 3. Ryan et. al, The Journal of Biological Chemistry, 1957, 225, pp. 103-114Early Examples
3. Cytochrome P450 OxidaseOverview: Cytochrome P450 Oxidases (CYPs) are the principal enzymes implicated in drug metabolism, catalyzing approximately 75% of reactions (1). The heme iron reacts with molecular oxygen and NADPH to produce a highly reactive intermediate called compound I.CYP Wiki Page: http://en.wikipedia.org/wiki/Cytochrome_P450 Drug Metabolism: http://en.wikipedia.org/wiki/Drug_metabolismOther References: 1. Guengerich, et. al. Chem. Res. Toxicol, 2008, 21 (1), pp 70–83 2. Axelrod, et. al, Journal of Pharmacology, 1955, vol. 114 no. 4, pp. 430-438 3. Ryan et. al, The Journal of Biological Chemistry, 1957, 225, pp. 103-114Mechanism
4. CYP and Tamoxifen MetabolismDehal et. al, Cancer Research, 1997, 57, pp. 3402-3406 Desta et. al, Journal of Pharmacology and Experimental Therapeutics, 2004, vol. 310 no. 3, pp. 1062-1075Shiau et. al, Cell, 1998, vol. 95 no. 7, pp. 927-937Tamoxifen, an antagonist of the estrogen receptor, is a prodrug used to treat breast cancer. Cytochrome P450s convert tamoxifen to active metabolites.N-Dealkylation converts tamoxifen to N-desmethyl tamoxifen, which is subsequently hydroxylated to form the active metabolite endoxifen.4-hydoxy-tamoxifen complexed with ligand-binding domain of estrogen receptor alpha (Shiau et. al.)
5. Problems1. Caraco et. al, Drug Metabolism and Disposition, 1996, vol. 24 no. 7, pp. 761-764 4. Dayton et. al, Drug Metabolism and Disposition, 1973, vol. 1 no. 6, pp. 742-7512. Claesen et. al, Drug Metabolism and Disposition, 1982, vol. 10 no. 6, pp. 667-671 3. Yoshii et. al, Life Sciences, 2000, vol. 67, no.2, pp. 175-1841. Hydroxylation of codeine by CYP2D6 yields a hemiacetal that spontaneously cleaves to an alcohol and formaldehyde. Propose an arrow-pushing mechanism for this decomposition under acidic and basic conditions.2. CYP2D6 oxidizes an aromatic pi bond in phenytoin to form an arene oxide intermediate that rapidly rearranges to a phenol via a mechanism called the NIH shift. Propose an arrow-pushing mechanism for this rearrangement.3. Predict the site of hydroxylation for the antipsychotic chlorpromazine. 4. The uricosuric drug probenecid undergoes no observable aromatic hydroxylation by CYPs. Explain this observation.
6. Contributed by: Created by Joseph Aman (Undergraduate)Edited by Margaret HiltonHonors Organic ChemistryChem 2321 (Sigman), 2013University of Utah