Abstract
As exposure to polycyclic aromatic hydrocarbons (PAHs; a family of environmental toxicants) have been implicated in cardiovascular diseases, the ability of the aortic tissue to process these toxicants is important from the standpoint of abdominal aortic aneurysms and atherosclerosis. Benzo(a)pyrene (B(a)P), a representative PAH compound is released into the environment from automobile exhausts, industrial emissions, and considerable intake of B(a)P is also expected in people who are smokers and barbecued red meat eaters. Therefore, knowledge of B(a)P metabolism in the cardiovascular system will be of importance in the management of vascular disorders. Toward this end, subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were isolated from the aortic tissues of Apo E mice that received a 5 mg/kg/week of B(a)P for 42 days and 0.71 mg/kg/day for 60 days. The fractions were incubated with 1 and 3 μM B(a)P. Post incubation, samples were extracted with ethyl acetate and analyzed by reverse-phase HPLC. Microsomal B(a)P metabolism was greater than the rest of the fractions. The B(a)P metabolite levels generated by all the subcellular fractions showed a B(a)P exposure concentration-dependent increase for both the weekly and daily B(a)P treatment categories. The preponderance of B(a)P metabolites such as 7,8-dihydrodiol, 3,6-, and 6,12-dione metabolites are interesting due to their reported involvement in B(a)P-induced toxicity through oxidative stress.
Similar content being viewed by others
References
Yang H, Zhou L, Wang Z, Roberts LJ 2nd, Lin X, Zhao Y, Guo Z (2009) Overexpression of antioxidant enzymes in ApoE-deficient mice suppresses benzo(a)pyrene-accelerated atherosclerosis. Atherosclerosis 207:51–58
Prins PA, Perati PR, Kon V, Guo Z, Ramesh A, Linton MF, Fazio S, Sampson UK (2012) Benzo[a]pyrene potentiates the pathogenesis of abdominal aortic aneurysms in apolipoprotein E knockout mice. Cell Physiol Biochem 29:121–130
Xu X, Hu H, Kearney GD, Kan H, Sheps DS (2013) Studying the effects of polycyclic aromatic hydrocarbons on peripheral arterial disease in the United States. Sci Total Environ 461–462:341–347
Environment Canada. (2007). Environment Canada.Ambient air measurements of polycyclicaromatichydro-carbons (PAH), polychlorinateddibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans in. Canada (1987–1997). Environmental technology center report, 2007
Murphy G Jr, Rouse RL, Polk WW, Henk WG, Barker SA, Boudreaux MJ, Floyd ZE, Penn AL (2008) Combustion-derived hydrocarbons localize to lipid droplets in respiratory cells. Am J Respir Cell Mol Biol 38:532–540
Wang Z, Yang H, Ramesh A, Roberts LJ 2nd, Zhou L, Lin X, Zhao Y, Guo Z (2009) Overexpression of Cu/Zn-superoxide dismutase and/or catalase accelerates benzo(a)pyrene detoxification by upregulation of the aryl hydrocarbon receptor in mouse endothelial cells. Free Radic Biol Med 47:1221–1229
Hough JL, Baird MB, Sfeir GT, Pacini CS, Darrow D, Wheelock C (1993) Benzo(a)pyrene enhances atherosclerosis in white carneau and show racer pigeons. Arterioscler Thromb Vasc Biol 13:1721–1727
Felton CV, Crook D, Davies MJ, Oliver MF (1997) Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol 17:1337–1345
Dreij K, Rhrissorrakrai K, Gunsalus KC, Geacintov NE, Scicchitano DA (2010) Benzo[a]pyrene diol epoxide stimulates an inflammatory response in normal human lung fibroblasts through a p53 and JNK mediated pathway. Carcinogenesis 31:1149–1157
Matsunawa M, Akagi D, Uno S, Endo-Umeda K, Yamada S, Ikeda K, Makishima M (2012) Vitamin D receptor activation enhances benzo[a]pyrene metabolism via CYP1A1 expression in macrophages. Drug Metab Dispos 40:2059–2066
Sampson UK, Perati PR, Prins PA, Pham W, Liu Z, Harrell FE Jr, Linton MF, Gore JC, Kon V, Fazio S (2011) Quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta for studies of abdominal aortic aneurysms and related arterial diseases. J Ultrasound Med 30:773–784
Ades IZ, Cascarano J (1977) Characterization of cytochrome oxidase purified from rat liver. J Bioenerg Biomembr 9:237–253
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Mantey JA, Rekhadevi PV, Diggs DL, Ramesh A (2014) Metabolism of benzo(a)pyrene by subcellular fractions of gastrointestinal (GI) tract and liver in ApcMin mouse model of colon cancer. Tumour Biol 35:4929–4935
Li J, Fan R, Lu S, Zhang D, Zhou Y, Ly Y (2014) Exposure to polycyclic aromatic hydrocarbons could cause their oxidative DNA damage: a case study for college students in Guangzhou, China. Environ Sci Pollut Res Int 22:1770–1777
Bolte G, Heitmann D, Kiranoglu M, Schierl R, Diemer J, Koerner W, Fromme H (2008) Exposure to environmental tobacco smoke in German restaurants, pubs and discotheques. J Expo Anal Environ Epidemiol 18:262–271
El-Mubarak AH, Rushdi AI, Al-Mutlaq KF, Bazeyad AY, Simonich SLM, Simoneit BRT (2014) Identification and source apportionment of polycyclic aromatic hydrocarbons in ambient air particulate matter of Riyadh, Saudi Arabia. Environ Sci Pollut Res Int 21:558–567
Aries E, Anderson DR, Fischer R (2008) Exposure assessment of workers to airborne PCDD/Fs, PCBs and PAHs at an electric arc furnace steelmaking plant in the United Kingdom. Ann Occup Hyg 52:213–225
Kuo C-Y, Chang S-H, Chien Y-C, Chiang F-Y, Wei Y-C (2006) Exposure to carcinogenic PAHs for the vendors of broiled food. J Expo Sci Environ Epidemiol 16:410–416
Ramesh A, Kumar A, Aramandla MP, Nyanda AM (2014) Polycyclic aromatic hydrocarbon residues in serum samples of autopsied individuals from Tennessee. Int J Environ Res Public Health 12:322–334
Naufal Z, Zhiwen L, Zhub L, Zhou GOD, McDonald T, He LY, Mitchell L, Renb A, Zhuc H, Finnellc R, Donnelly KC (2010) Biomarkers of exposure to combustion by-products in a human population in Shanxi, China. J Expo Sci Environ Epidemiol 20:310–319
Aylward LL, Kirman CR, Adgate JL, McKenzie LM, Hays SM (2009) Interpreting variability in population biomonitoring data: role of elimination kinetics. J Expo Sci Environ Epidemiol 22:398–408
Lynch T, Price A (2007) The effect of cytochrome P450 metabolism on drug interactions and adverse effects. Am Fam Physician 76:391–396
INCHEM (1986). Principles of toxicokinetic studies. Environmental health criteria 57. International programme on chemical safety, World Health Organization, Geneva
Wall KL, Gao WS, te Koppele JM, Kwei GY, Kauffman FC, Thurman RG (1991) The liver plays a central role in the mechanism of chemical carcinogenesis due to polycyclic aromatic hydrocarbons. Carcinogenesis 12:783–786
Zhao W, Parrish AR, Ramos KS (1998) Constitutive and inducible expression of cytochrome P450IA1 and P450IB1 in human vascular endothelial and smooth muscle cells. In Vitro Cell Dev Biol 34:671–673
Miller KP, Ramos KS (2007) Molecular mechanisms of environmental atherogenesis. In: Holtzman JL (ed) Atherosclerosis and oxidant stress. Springer, New York, pp 159–210
Gelboin HV (1980) Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol Rev 60:1107–1166
Fujii-Kuriyama Y, Mimura J (2005) Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun 38:311–317
Kerzee JK, Ramos KS (2001) Constitutive and inducible expression of Cyp1a1 and Cyp1b1 in vascular smooth muscle cells: role of the Ahr bHLH/PAS transcription factor. Circ Res 89:573–582
Uno S, Sakurai K, Nebert DW, Makishima M (2014) Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta. Toxicology 316:34–42
Kerley-Hamilton JS, Trask HW, Ridley CJ, Dufour E, Lesseur C, Ringelberg CS, Moodie KL, Shipman SL, Korc M, Gui J, Shworak NW, Tomlinson CR (2012) Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice. Toxicol Sci 126:391–404
Zhang Y, Ramos KS (2008) The development of abdominal aortic aneurysms in mice is enhanced by benzo(a)pyrene. Vasc Health Risk Manag 4:1095–1102
Ji K, Zhang Y, Jiang F, Qian L, Guo H, Hu J, Liao L, Tang J (2014) Exploration of the mechanisms by which 3,4-benzopyrene promotes angiotensin II-induced abdominal aortic aneurysm formation in mice. J Vasc Surg Cases 59:492–499
Daugherty A, Manning MW, Cassis LA (2000) Angiotensin Ii promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 105:1605–1612
Rateri AL, Davis FM, Balakrishnan A, Howatt DA, Moorleghen JJ, O’Connor WN, Chamigo R, Cassis LA, Daugherty A (2014) Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. Am J Pathol 184:2586–2595
Jennings BL, Moore JA, Pingili AK, Estes AM, Fang XR, Kanu A, Gonzalez FJ, Malik KU (2015) Disruption of the cytochrome P450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice. Am J Physiol Renal Physiol 308:F981–F992
Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, Sagara J, Taniguchi S, Takahashi M (2015) Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm. Arterioscler Thromb Vasc Biol 35:127–136
Diggs DL, Harris KL, Rekhadevi PV, Ramesh A (2012) Tumor microsomal metabolism of the food toxicant, benzo(a)pyrene, in ApcMin mouse model of colon cancer. Tumour Biol 33:1255–1260
Sarti P, Lendaro E, Ippoliti R, Bellelli A, Benedetti PA, Brunori M (1999) Modulation of mitochondrial respiration by nitric oxide: investigation by single cell fluorescence microscopy. FASEB J 13:191–197
Roos PH (2002) Differential induction of CYP1A1 in duodenum, liver and kidney of rats after oral intake of soil containing polycyclic aromatic hydrocarbons. Arch Toxicol 76:75–82
Miller KP, Ramos KS (2001) Impact of cellular metabolism on the biological effects of benzo(a)pyrene and related hydrocarbons. Drug Metab Rev 33:1–35
Li X, Feng Y, Deng H, Zhang W, Kuang D, Deng Q, Dai X, Lin D, Huang S, Xin L, He Y, Huang KH (2012) The dose-response decrease in heart rate variability: any association with the metabolites of polycyclic aromatic hydrocarbons in coke oven workers. PLoS ONE 7:e44562
Everett CJ, King DE, Player MS, Matheson EM, Post RE, Mainous AG 3rd (2010) Association of urinary polycyclic aromatic hydrocarbons and serum C-reactive protein. Environ Res 110:79–82
Acknowledgments
The research embodied in this manuscript was facilitated by The Harold Amos Faculty Development Award of the Robert Wood Johnson Foundation (Princeton, NJ), and the Vanderbilt Clinical and Translational Scholars Award to UKS. Also, funding support through the National Institutes of Health (NIH) Grants 5S11ES01415602 from the National Institute of Environmental Health Sciences (NIEHS) to UKS and AR, 5RO1CA142845-04 from the National Cancer Institute (NCI) to AR is acknowledged. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NIH or Vanderbilt University or Meharry Medical College.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they do not have any conflicts of interest.
Rights and permissions
About this article
Cite this article
Ramesh, A., Prins, P.A., Perati, P.R. et al. Metabolism of benzo(a)pyrene by aortic subcellular fractions in the setting of abdominal aortic aneurysms. Mol Cell Biochem 411, 383–391 (2016). https://doi.org/10.1007/s11010-015-2600-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-015-2600-2