Speciation, metabolism, toxicity, and protein-binding of different arsenic species in human cells

Despite of its known toxicity and potential to cause cancer, arsenic has been proven to be a very important tool for the treatment of various refractory neoplasms. One of the promising arsenic-containing chemotherapeutic agents in clinical trials is Darinaparsin (dimethylarsinous glutathione, DMA III(GS)). In order to understand its toxicity and therapeutic efficacy, the metabolism of Darinaparsin in human cancer cells was evaluated. With the aim of detecting all potential intermediates and final products of the biotransformation of Darinaparsin and other arsenicals, an analytical method employing high performance liquid chromatography inductively coupled mass spectrometry (HPLC-ICP-MS) was developed. This method was shown to be capable of separating and detecting fourteen human arsenic metabolites in one chromatographic run. The developed analytical technique was used to evaluate the metabolism of Darinaparsin in human cancer cells. The major metabolites of Darinaparsin were identified as dimethylarsinic acid (DMAV), DMA III(GS), and dimethylarsinothioyl glutathione (DMMTAV(GS)). Moreover, the method was employed to study the conditions and mechanisms of formation of thiol-containing arsenic metabolites from DMAIII(GS) and DMAV as the mechanisms of formation of these important As species were unknown. The arsenic sulfur compounds studied included but were not limited to the newly discovered human arsenic metabolite DMMTA V(GS) and the unusually highly toxic dimethylmonothioarsinic acid (DMMTAV). It was found that these species may form from hydrogen sulfide produced in enzymatic reactions or by utilizing the sulfur present in protein persulfides. Possible pathways of thiolated arsenical formation were proposed and supporting data for their existence provided. In addition to known mechanism of arsenic toxicity such as protein-binding and reactive oxygen formation, it was proposed that the utilization of thiols from protein persulfides during the formation of thiolated arsenicals may be an additional mechanism of toxicity. The toxicities of DMAV(GS), DMMTA V, and DMMTAV(GS) were evaluated in cancer cells, and the ability of these cells to take the compounds up were compared. When assessing the toxicity by exposing multiple myeloma cells to arsenicals externally, DMMTAV(GS) was much less toxic than DMAIII(GS) and DMMTAV, probably as a result of its very limited uptake (less than 10% and 16% of DMAIII(GS) and DMMTAV respectively).^

The Effect of Carbohydrate Amount, Quality and Type on Arterial Pulse Pressure in Cuban-Americans with and Without Type 2 Diabetes

Background: Arterial pulse pressure, the difference between systolic and diastolic blood pressure, has been used as an indicator (surrogate measure) of arterial stiffness. High arterial pulse pressure (> 40) has been associated with increased cardiovascular disease and mortality. Several clinical trials have reported that the proportion of calories from carbohydrate has an effect on blood pressure. The primary objective of this study was to assess arterial pulse pressure and its association with carbohydrate quantity and quality (glycemic load) with diabetes status for a Cuban American population. Methods: A single point analysis included 367 participants. There was complete data for 365 (190 with and 175 without type 2 diabetes). The study was conducted in the investigator’s laboratory located in Miami, Florida. Demographic, dietary, anthropometric and laboratory data were collected. Arterial pulse pressure was calculated by the formula systolic minus the diastolic blood pressure. Glycemic load, fructose, sucrose, percent of average daily calories from carbohydrate, fat and protein, grams of fiber and micronutrient intakes were calculated from a validated food frequency questionnaire. Results: The mean arterial pulse pressure was significantly higher in participants with (52.9 ± 12.4) than without (48.6 ± 13.4) type 2 diabetes. The odds of persons with diabetes having high arterial pulse pressure (>40) was 1.85 (95% CI =1.09, 3.13); p=0.023. For persons with type 2 diabetes higher glycemic load was associated with lower arterial pulse pressure. Conclusions: Arterial pulse pressure and diet are modifiable risk factors of cardiovascular disease. Arterial pulse pressure may be associated with carbohydrate intake differently considering diabetes status. Results may be due to individuals with diabetes following dietary recommendations. The findings of this study suggest clinicians take into consideration how medical condition, ethnicity and diet are associated with arterial pulse pressure before developing a medical nutrition therapy plan in collaboration with the client.