Cytochrome P450 (P450) enzymes are involved in the oxidations of ~95% of chemicals, including many drugs, steroids, and chemical carcinogens. Variations in P450s are issues in drug-drug interactions, endocrine diseases, cancer, and other medical problems.
One Aim i s the identification of functions of orphan P450s. We identified skin mitochondrial P450 27C1 as a retinoid 3,4-desaturase, but the function of 3,4-dehydroretinoids is unknown. Studies are focused on human keratinocytes and include immunohistochemical localization, subcellular location, absolute quantitation of P450 27C1 and redox partners in skin using proteomics, roles of retinoid binding proteins, analysis of effects of relevant retinoids on keratinocytes, examination of inducibility by retinoids and light, promoter analysis, and analysis of genes regulated by P450 27C1 desaturation, in order to define the function of this enzyme. We also plan to use LC-MS metabolomic screens to identify endogenous substrates for human P450s 2S1, 4X1, and 20A1. We will also screen Cyp2s1?/? vs. wild-type mice and a zebrafish P450 20A1 knockout model. A mechanism of human P450 51A1 (lanosterol 14a-demethylase) is proposed involving Compound I (FeO3+), which will be addressed using an isotopic labeling approach with 2H- labeled 32-formyl lanosterol and analysis of the side product formic acid. Detailed kinetic approaches will be applied to the question of the complex 3-step oxidation of deoxycorticosterone to the important steroid aldosterone by P450 11B2, a drug target in hypertension. These kinetic approaches to analysis of processivity will be applied to several other human P450s. Collectively the proposed experiments will provide useful information about the functions and mechanisms of several human P450s and have continued relevance in the fields of endocrinology and drug metabolism.

Public Health Relevance

Many of the chemicals that cause cancer are made either more or less active by cytochrome P450 (P450) enzymes in the body. Three enzymes are also involved in the metabolism of drugs, including those used to treat cancer. The enzymes are also involved in the metabolism of steroids and influence hormone action.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Garcia, Martha
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Lee, Yeon J; Wang, Qingqing; Rio, Donald C (2018) Coordinate regulation of alternative pre-mRNA splicing events by the human RNA chaperone proteins hnRNPA1 and DDX5. Genes Dev 32:1060-1074
Albertolle, Matthew E; Phan, Thanh T N; Pozzi, Ambra et al. (2018) Sulfenylation of Human Liver and Kidney Microsomal Cytochromes P450 and Other Drug-Metabolizing Enzymes as a Response to Redox Alteration. Mol Cell Proteomics 17:889-900
Rendic, Slobodan P; Guengerich, Frederick P (2018) Development and Uses of Offline and Web-Searchable Metabolism Databases - The Case of Benzo[a]pyrene. Curr Drug Metab 19:3-46
Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877
Gonzalez, Eric; Johnson, Kevin M; Pallan, Pradeep S et al. (2018) Inherent steroid 17?,20-lyase activity in defunct cytochrome P450 17A enzymes. J Biol Chem 293:541-556
Soucek, Pavel; Vrana, David; Ueng, Yune-Fang et al. (2018) Selective changes in cholesterol metabolite levels in plasma of breast cancer patients after tumor removal. Clin Chem Lab Med 56:e78-e81
Albertolle, Matthew E; Peter Guengerich, F (2018) The relationships between cytochromes P450 and H2O2: Production, reaction, and inhibition. J Inorg Biochem 186:228-234
Marsch, Glenn A; Carlson, Benjamin T; Guengerich, F Peter (2018) 7,8-benzoflavone binding to human cytochrome P450 3A4 reveals complex fluorescence quenching, suggesting binding at multiple protein sites. J Biomol Struct Dyn 36:841-860
Shimada, Tsutomu; Murayama, Norie; Kakimoto, Kensaku et al. (2018) Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants. Xenobiotica 48:565-575
Johnson, Kevin M; Phan, Thanh T N; Albertolle, Matthew E et al. (2017) Human mitochondrial cytochrome P450 27C1 is localized in skin and preferentially desaturates trans-retinol to 3,4-dehydroretinol. J Biol Chem 292:13672-13687

Showing the most recent 10 out of 36 publications