Cancers and cardiovascular diseases constitute major health problems and are the main causes of premature mortality. Polycyclic aromatic hydrocarbons (PAHs) are distributed widely and persistently in our environments. A variety of toxicities, including carcinogenicity and atherogenesis, are caused by PAHs. Several reports suggest that the metabolic activation of PAHs by cytochrome P450s (CYPs) is a necessary step for PAH-induced carcinogenesis and atherosclerosis. The expressions of CYP1A1/1B1 are induced by PAHs via aryl hydrocarbon receptor (AhR). The CYP1A1 bioactivates PAHs, such as 7, 12- dimethylbenz(a)anthracene (DMBA). Several lines of experimental evidence show a link between environmental carcinogens and breast cancer risk. Recent reports demonstrate that PAHs inhibit Liver X receptor (LXR)-mediated signal transductions through AHR, which are known to maintain the cholesterol homeostasis. The P450 system plays an important role in modulation of cardiovascular physiology and pathophysiology. The major mechanisms of chemoprotection involve induction of phase II detoxification enzymes and/or inhibition of phase I enzymes (CYP1A1, 1A2, 1B1) that are involved in the activation of certain carcinogens. Atherosclerosis involves three processes, oxidation, inflammation and hypercholesterolemia. Phytochemicals have the advantage of being dietary and natural compounds that are less toxic to animals, abundant, and inexpensive. Recent studies suggests that curcumin and sulforaphane are highly promising dietary phytochemicals, due to their ability to confer protection through several distinct pathways and via multiple mechanisms of action. We studied the anti-carcinogenic potencies of sulforaphane and curcumin against DMBA induced mammary tumorigenesis in female mice. We also studied the anti-atherogenic potential of these phytochemicals in mice exposed to PAHs. The dietary phytochemicals significantly reduced the PAH induced CYP1A1/1B1 and AHR activities in hepatic, mammary, heart and aorta of mice along with induction of phase II enzymes. These results show the strong antioxidant potential of the phytochemicals. The PAH-DNA adduct formation was observed in aortic smooth muscle cells, mouse mammary and hepatic tissues. Atherosclerotic lesion formation was higher in wild type mice compared to AHR knockout mice. The information gained from these studies will aid in the development of effective prevention and treatment strategies of cancers and cardiovascular diseases involving dietary constituents with a broad spectrum of beneficial effects.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2703.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO