RESUMEN
The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which upon activation by its agonists, translocates into the nucleus and forms a dimer with ARNT (aryl hydrocarbon nuclear translocator). The AHR/ARNT dimer regulates the expression of its target genes by binding to DNA recognition elements termed dioxin responsive elements (DREs). Many AHR agonists, like the polyaromatic hydrocarbons and polyhalogenated hydrocarbons are known human carcinogens. Human exposure to these compounds is common due to their presence in air pollution and cigarette smoke. Interestingly, many dietary constituents that have chemo preventative properties have been found to also act as antagonists of the AHR pathway. Thus, a chemopreventive approach that may be effective in decreasing the incidences of many human cancers may involve a dietary regimen that includes a number of these naturally occurring AHR antagonists. With this idea in mind, we have assayed the ability of 15 flavonoids to inhibit AHR activated reporter activity and selected kaempferol for further analysis. Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. Using an in vitro paradigm of events that are thought to occur during cigarette-smoke-induced lung cancer, we found that kaempferol also inhibited the ability of cigarette smoke condensate to induce growth of immortalized lung epithelial (BEAS-2B) cells in soft agar. Taken together, these results illustrate the promise associated with the use of flavonoids, that inhibit both AHR signaling and the carcinogenic actions of AHR agonists, for chemopreventive purposes.
Asunto(s)
Transformación Celular Neoplásica , Quempferoles/farmacología , Receptores de Hidrocarburo de Aril/fisiología , Fumar/efectos adversos , Anticarcinógenos/farmacología , Carcinoma Hepatocelular , Línea Celular Tumoral , Dimetilsulfóxido/farmacología , Flavanonas/farmacología , Flavonas/farmacología , Flavonoides/farmacología , Humanos , Trasplante de Hígado , Luteolina/farmacología , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Resveratrol , Estilbenos/farmacologíaRESUMEN
PURPOSE: It is reported that 25% to 50% of patients with abdominal aortic aneurysms (AAA) have severe coronary artery disease (CAD) and should undergo an aggressive cardiac workup before AAA repair. In contrast, it has been our policy that patients referred for AAA repairs undergo no cardiac testing before surgery. METHODS: This report reviews the last 113 consecutive patients who underwent elective AAA repair by the senior author using this policy. Seventy-four patients (group A) had only an electrocardiogram before surgery. The remaining 39 patients (group B) were referred having already had additional testing that included a thallium stress test (n = 20), echocardiogram (n = 18), multiple gated acquisition (MUGA) scan (n = 3), cardiac catheterization (n = 8), or some combination of these. RESULTS: There was no statistical difference between group A and group B with regard to age, sex, tobacco use or history of coronary artery disease, diabetes mellitus, stroke (CVA), hypertension, peripheral vascular disease, or chronic obstructive pulmonary disease. Group B more commonly had a history of myocardial infarction (41% vs 19%, p < 0.03) and congestive heart failure (23% vs 7%, p < 0.03). During surgery there was no significant differences in blood loss, transfusion requirements, or operative times. There were no myocardial infarctions in group A and two (5.1%) in group B, which was not significantly different. Other complications, such as CVA, renal failure, pulmonary failure, pneumonia, wound infection, and hemorrhage, were not significantly different between the two groups. Postoperative hospital stay was not significantly different. There were three deaths in the entire series (2.7%), and only one in group B was cardiac-related in a patient with known end-stage cardiac disease and a symptomatic 8 cm AAA. CONCLUSIONS: These data indicate that most patients with AAA can safely undergo repair with no cardiac workup and that cardiac workup before AAA repair contributes little information that impacts on treatment or final clinical outcome. We conclude that cardiac testing in preparation for AAA repair is not usually necessary and that intraoperative hemodynamic management may be the most important variable in determining outcome.