Effect of Polyaryl Hydrocarbons on Cytotoxicity in Monocytic Cells: Potential Role of Cytochromes P450 and Oxidative Stress Pathways.
BACKGROUND
Benzo(a)pyrene (BaP), naphthalene (NPh), phenanthrene (Phe), benzo(a)antharacene (BeA), and benzo(b)fluoranthene (BeF) are known carcinogenic polyaryl hydrocarbons (PAHs) present in cigarette smoke. This study was designed to examine the relative effect of these constituents on the cytotoxicity of monocytic cells and the possible mechanism of PAH-mediated cytotoxicity.


METHODS
We examined the acute (6-24 hours) and chronic (7 days) effects of these PAHs on the expression of cytochromes P450 (CYPs), oxidative stress, and cytotoxicity. The treated cells were examined for mRNA and protein levels of CYPs (1A1 and 3A4) and antioxidants enzymes (AOEs) superoxide dismutase-1 (SOD1) and catalase. Further, we assessed the levels of reactive oxygen species (ROS), caspase-3 cleavage activity, and cell viability. We performed these experiments in U937 and/or primary monocytic cells.


RESULTS
Of the five PAHs tested, after chronic treatment only BaP (100 nM) showed a significant increase in the expression of CYP1A1, AOEs (SOD1 and catalase), ROS generation, caspase-3 cleavage activity, and cytotoxicity. However, acute treatment with BaP showed only an increase in the mRNA expression of CYP1A1.


CONCLUSIONS
These results suggest that of the five PAHs tested, BaP is the major contributor to the toxic effect of PAHs in monocytic cells, which is likely to occur through CYP and oxidative stress pathways.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Sabina
S
Ranjit
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Narasimha M
NM
Midde
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Namita
N
Sinha
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Benjamin J
BJ
Patters
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Mohammad A
MA
Rahman
Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Theodore J
TJ
Cory
Department of Pharmaceutical Sciences, The University of Findley, 1000 N. Main Street, Findlay, OH, 45840, United States of America.
P S S
PS
Rao
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
Santosh
http://orcid.org/0000-0001-7846-5674
S
Kumar
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