# Metabolism of Carcinogens and Drugs by Human P450s

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $444,983

## Abstract

SUMMARY
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 is 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.

## Key facts

- **NIH application ID:** 10383718
- **Project number:** 5R01GM118122-22
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** F PETER Guengerich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,983
- **Award type:** 5
- **Project period:** 2001-05-20 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383718

## Citation

> US National Institutes of Health, RePORTER application 10383718, Metabolism of Carcinogens and Drugs by Human P450s (5R01GM118122-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10383718. Licensed CC0.

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