# Mechanistic role of P4501 enzymes in the prevention of PAH carcinogenesis by omega 3 fatty acids

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $448,917

## Abstract

PROJECT SUMMARY
The cytochrome P450s (CYPs) are the major enzymes involved in drug metabolism and bioactivation. It is well
known that several CYP enzymes metabolize omega-3 fatty acids to their epoxy metabolites that inhibit
angiogenesis, tumor growth, and metastasis. Numerous polycyclic aromatic hydrocarbons (PAH) are human
carcinogens. PAH-DNA adducts may lead to DNA damage and mutations in critical genes, eventually leading
to cancer. A significant positive linear regression between levels of PAH-DNA adducts and tumor incidence
was observed in animal experiments in our laboratory. We also discovered that omega-3 fatty acids
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) inhibited CYP1B1, EZH2, DNMT3a, miR 17,
miR19b-1 and significantly decreased pulmonary and hepatic PAH-DNA adducts, and tumor incidence. The
central hypothesis of this application is that omega 3-fatty acids and their epoxy metabolites will attenuate
pulmonary carcinogenesis by multiple mechanisms entailing attenuation of PAH-DNA adduct formation by
modulating CYPs, as well as by suppression of tumorigenesis, probably via modulation of epigenetic genes
(e.g., EZH2, DNMT3a, miR-17, miR-19b-1). We propose the following Specific Aims. Aim 1: To test the
hypothesis that CYP1A1 and CYP1B1 play mechanistic roles in prevention of PAH carcinogenesis in mice
maintained on EPA, DHA, or EPA + DHA diets, compared to those on a CO diet, followed by exposure of
these mice to BP for the study of the mechanisms. Aim 2: To test the hypothesis that mice deficient in soluble
epoxide hydrolase (sEH) will confer more protection than WT mice to EPA/DHA-mediated prevention of PAH
carcinogenesis, as sEH is known to rapidly hydrolyze epoxy metabolites such as 17,18-epoxy eicosatetraenoic
acid (EEQ) and 19,20-epoxy docosapentaenoic acids (EDP) in serum and tissues to inactive metabolites. In
some experiments, we will treat WT mice with the specific sEH inhibitor, t-TUCB, or a new t-TUCB-like inhibitor
(that is likely to go to human clinical trials soon), followed by treatment of mice with EPA/DHA and BP. Aim 3:
To test the hypothesis that endogenous omega-3 fatty acids, especially their epoxy metabolites, will play a
pivotal role in the prevention of pulmonary carcinogenesis by PAHs in vivo, and that there is a mechanistic link
between CYP1, and sEH. Fat-1-transgenic (Fat-1-Tg) mice, which will convert endogenous omega-6 fatty
acids (rich in CO) into omega-3 fatty acids and decrease the ratios of omega-6/omega-3, will be used in this
study. We will also create Fat-1-Tg/sEH-null mice for exploring the mechanisms by which CYP1 and sEH
enzymes contribute to omega-3 fatty acid-mediated prevention of PAH carcinogenesis. If our hypothesis that
CYP1 and sEH enzymes play important roles in omega-3 fatty acids, i.e. EPA/DHA-mediated prevention of
PAH-induced cancers turns out to be correct, then it will break new grounds in the current understanding of
human cancer prevention. If successful, the propos...

## Key facts

- **NIH application ID:** 10404072
- **Project number:** 5R01ES029382-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** BHAGAVATULA MOORTHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $448,917
- **Award type:** 5
- **Project period:** 2018-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404072

## Citation

> US National Institutes of Health, RePORTER application 10404072, Mechanistic role of P4501 enzymes in the prevention of PAH carcinogenesis by omega 3 fatty acids (5R01ES029382-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10404072. Licensed CC0.

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