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Cardiovascular Research 2002 53(4):1002-1009; doi:10.1016/S0008-6363(01)00536-3
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

The atherogen 3-methylcholanthrene induces multiple DNA adducts in mouse aortic smooth muscle cells: role of cytochrome P4501B1

Bhagavatula Moorthya,*, Kimberly P. Millerb, Weiwu Jianga and Kenneth S. Ramosb

aDepartment of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
bFaculty of Toxicology and Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA

bmoorthy{at}bcm.tmc.edu

* Corresponding author. Tel.: +1-713-798-6185; fax: +1-713-798-5691

Objective: 3-Methylcholanthrene (MC), a polycylic aromatic hydrocarbon, induces atherogenesis in mice fed an atherogenic diet. In this study, we tested the hypothesis that MC would induce DNA adducts in mouse aortic smooth muscle cells (SMCs) and that cytochrome P4501B1 (CYP1B1) plays an important role in the activation of MC to genotoxic intermediates. Methods: Cultured SMCs were treated with MC or the vehicle dimethyl sulfoxide (DMSO), and DNA was isolated after 24 h. In some experiments, the cells were pre-treated with the CYP1B1 inhibitor 1-ethynylpyrene (EP) prior to exposure to MC. DNA adducts were determined by the 32P-postlabeling assay. Aryl hydrocarbon hydroxylase assay was measured by fluorimetry. Results: MC induced formation of 12 DNA adducts that were not observed in DMSO-treated cells. DNA adduct formation was dose-dependent, with maximum response observed at 3 µM. Pre-treatment of cells with EP dramatically suppressed DNA adduct formation by MC. MC treatment caused induction of CYP1B1, but not CYP1A1. Conclusion: The induction of high levels of multiple DNA adducts in SMCs by MC suggests that SMCs have a functional enzymatic machinery capable of metabolically activating MC to genotoxic metabolites. The significant inhibition by EP of MC-induced DNA adduct formation indicated that CYP1B1 was the primary CYP enzyme responsible for formation of genotoxic metabolites that may play a role in the induction of atherosclerosis by MC.

KEYWORDS Atherosclerosis; Cell culture/isolation; Free radicals; Signal transduction; Smooth muscle


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