Polycyclic Aromatic Hydrocarbon-induced Pulmonary Carcinogenesis in Cytochrome P450 (CYP)1A1- and 1A2-Null Mice: Roles of CYP1A1 and CYP1A2
Year: 2020
Type: article
Abstract: In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and 1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type, Cyp1a1-null (Cyp1a1-/-), and Cyp1a2-null (Cyp1a2-/-) male and female mice were treated with 3-methylcholanthrene for cancer initiation and tumor formation studies. In wild-type mice, CYP1A1 and 1A2 expression was induced by 3-methylcholanthrene. Cyp1a1-/- and Cyp1a2-/- mice treated with PAHs displayed a compensatory pattern, where knocking out 1 Cyp1a gene led to increased expression of the other. Cyp1a1-/- mice were resistant to DNA adduct and tumor formation, whereas Cyp1a2-/- mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1-/- mice were less susceptible to PAH-induced pulmonary carcinogenesis, whereas Cyp1a2-/- mice were more susceptible. In addition, high CYP1A2 expression was found to be protective for lung adenocarcinoma patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.
Source: Toxicological Sciences
Authors: Grady Gastelum, Weiwu Jiang, Lihua Wang, Guodong Zhou, Roshan Borkar, Nagireddy Putluri, Bhagavatula Moorthy
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
Funders: American Cancer Society, Cancer Prevention and Research Institute of Texas, Dan L. Duncan Cancer Center, Baylor College of Medicine, National Institutes of Health, U.S. Public Health Service, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Environmental Health Sciences
Awards: Identify the DNA Adduct and Associated Metabolic Alterations in Bladder Cancer of Smokers, Racial Disparity in Bladder Cancer and Identification of Altered Metabolism in African American Compare to European Bladder Cancer, Mechanisms of Prevention of Polycyclic Aromatic Hydrocarbon (PAH)–Mediated Lung Carcinogenesis by Omega-3 Fatty Acids, Role of cytochrome P4501B1 in oxygen-mediated pulmonary injury, G2965821721, Elucidating the Role of Xenobiotic Metabolism in Bladder Cancer Progression, Molecular mechanisms of cytochrome P4501A regulation by hyperoxia, Molecular mechanism of cytochrome P4501A1 expression., Functional roles of Nrf2 and NQO1 genetic variants in hyperoxic lung injury-ARDS, G5554127227, Mechanistic roles of Cytochrome P4501A enzymes in hyperoxic lung injury, Mechanistic role of P4501 enzymes in the prevention of PAH carcinogenesis by omega 3 fatty acids, G7639811720, G8052300427, Roles of pulmonary and hepatic P4501A enzymes in hyperoxic lung injury in mice, Circulating Biomarkers and Imaging for Early Detection of Pancreatic Cancer, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION,EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONICLUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION ANDREMEDIATION
OpenAlex ID: W3045806320