1. Cytochrome P450 Oxidase Created by Joseph Aman
Edited by Margaret Hilton
Honors Organic Chemistry
Chem 2321 (Sigman), 2013

2. Cytochrome P450 Oxidase
Overview: 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.
Early Examples
CYP Wiki Page: Drug Metabolism:
Other References: Guengerich, et. al. Chem. Res. Toxicol, 2008, 21 (1), pp 70– Axelrod, et. al, Journal of Pharmacology, 1955, vol. 114 no. 4, pp Ryan et. al, The Journal of Biological Chemistry, 1957, 225, pp

3. Cytochrome P450 Oxidase
Overview: 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.
Mechanism
CYP Wiki Page: Drug Metabolism:
Other References: Guengerich, et. al. Chem. Res. Toxicol, 2008, 21 (1), pp 70– Axelrod, et. al, Journal of Pharmacology, 1955, vol. 114 no. 4, pp Ryan et. al, The Journal of Biological Chemistry, 1957, 225, pp

4. CYP and Tamoxifen Metabolism
Tamoxifen, an antagonist of the estrogen receptor, is a prodrug used to treat breast cancer. Cytochrome P450s convert tamoxifen to active metabolites.
4-hydoxy-tamoxifen complexed with ligand-binding domain of estrogen receptor alpha (Shiau et. al.)
N-Dealkylation converts tamoxifen to N-desmethyl tamoxifen, which is subsequently hydroxylated to form the active metabolite endoxifen.
Dehal et. al, Cancer Research, 1997, 57, pp
Desta et. al, Journal of Pharmacology and Experimental Therapeutics, 2004, vol. 310 no. 3, pp
Shiau et. al, Cell, 1998, vol. 95 no. 7, pp

5. Problems
1. 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.
1. Caraco et. al, Drug Metabolism and Disposition, 1996,  vol. 24 no. 7, pp Dayton et. al, Drug Metabolism and Disposition, 1973, vol. 1 no. 6, pp
2. Claesen et. al, Drug Metabolism and Disposition, 1982, vol. 10 no. 6, pp  
3. Yoshii et. al, Life Sciences, 2000, vol. 67, no.2, pp

6. Contributed by: Created by Joseph Aman (Undergraduate)
Edited by Margaret Hilton
Honors Organic Chemistry
Chem 2321 (Sigman), 2013
University of Utah