Ronald F. Chanderbhan

Effects of α‐tocopherol and β‐carotene on hepatic lipid peroxidation and blood lipids in rats with dietary iron overload

Abstract The ability of dietary antioxidants to reduce lipid peroxidation induced by iron overload was examined in weanling male Sprague‐Dawley rats. Animals were fed ad libitum a modified AIN‐76A diet (control) or control diet with 0.5% α‐tocopherol acid succinate, 0.5% crystalline trans‐β‐carotene, or 0.5% α‐tocopherol acid succinate + 0.5% trans‐β‐carotene for four weeks. In the following four‐week period, the animals received the above diets with 10,000 μg Fe/g; a control group continued to receive 35 μg Fe/g, and a high‐iron group received 10,000 μg Fe/g with no antioxidants. After four weeks of dietary supplementation with α‐tocopherol, β‐carotene, or α‐tocopherol + β‐carotene, liver concentrations of α‐tocopherol and β‐carotene increased significantly (p < 0.001). Liver lipid peroxidation, measured by the lipid‐conjugated diene assay, increased significantly from 0.012 μmol/mg of lipid in the controls to 0.021 μmol/mg of lipid in animals receiving the high‐iron diet. However, lipid peroxidation was...

In Silico Toxicological Screening of Natural Products

ABSTRACT This study closely examines six well-known naturally occurring dietary chemicals (estragole, pulegone, aristolochic acid I, lipoic acid, 1-octacosanol, and epicatechin) with known human exposure, chemical metabolism, and mechanism of action (MOA) using in silico screening methods. The goal of this study was to take into consideration the available information on these chemicals in terms of MOA and experimentally determined toxicological data, and compare them to the in silico predictive modeling results produced from a series of computational toxicology software. After these analyses, a consensus modeling prediction was formulated in light of the weight of evidence for each natural product. We believe this approach of examining the experimentally determined mechanistic data for a given chemical and comparing it to in silico generated predictions and data mining is a valid means to evaluating the utility of the computational software, either alone or in combination with each other. We find that consensus predictions appear to be more accurate than the use of only one or two software programs and our in silico results are in very good agreement with the experimental toxicity data for the natural products screened in this study.

Effect of increasing iron supplementation on blood lipids in rats

The effects of increasing levels of Fe on serum fatty acids, cholesterol, triacylglycerol, liver and heart were examined in male Sprague-Dawley rats fed either Fe-deficient or carbonyl Fe-supplemented diets with 35 (control), 350, 3500 and 20 000 microg Fe/g for 12 weeks. As intake of Fe increased, serum total cholesterol increased from 2.0 mmol/l in controls to 5.2 mmol/l at the highest level of Fe. Also, the total serum phospholipid fatty acids increased from 609 mg/dl in controls to 1292 mg/l at the highest level of Fe. Except for the highest dose of Fe, the ratio of saturated to unsaturated phospholipid fatty acids increased from 1.2 to 1.7. The serum total free fatty acid levels remained constant among all groups with a range from 162 to 228 mg/l, while a ratio of 0.6 to 0.8 for saturated to unsaturated fatty acids was maintained. A dose-related increase in liver non-haem Fe from 18 to 3500 microg/g correlated with increases in lipid peroxidation (r 0.87), measured by the lipid-conjugated diene assay. Oxidative changes in the liver may have resulted in alterations in sterol synthesis, leading to increased serum cholesterol levels with increases in serum phospholipids and changes in the ratios of their saturated to unsaturated fatty acids. Animals with heart damage showed myocardial degeneration and cardiomyopathy with haemosiderin in interstitial macrophages or myocardial fibres and, when these were coupled with the findings of increased non-haem Fe in the heart and lipid peroxidation in the liver, suggested that oxidative stress is involved in the pathogenesis of the lesions.

Regulatory use of computational toxicology tools and databases at the United States Food and Drug Administration's Office of Food Additive Safety.

Over 10 years ago, the Office of Food Additive Safety (OFAS) in the FDAs Center for Food Safety and Applied Nutrition implemented the formal use of structure–activity relationship analysis and quantitative structure–activity relationship (QSAR) analysis in the premarket review of food-contact substances. More recently, OFAS has implemented the use of multiple QSAR software packages and has begun investigating the use of metabolism data and metabolism predictive models in our QSAR evaluations of food-contact substances. In this article, we provide an overview of the programs used in OFAS as well as a perspective on how to apply multiple QSAR tools in the review process of a new food-contact substance.

The Biology of Nutrients: Genetic and Molecular Principles

Abstract The intake of nutrients for growth, repair, and energy is an age-old, intuitive concept of nutrition regarding the role of nutrients in the body. Unlike treating diseases with drug interventions, treating adverse nutritional consequences (e.g., obesity) with nutritional intervention has remained elusive. This is, at least in part, due to the acute nature of the adverse effects of disease as opposed to the chronic nature of the adverse effects of inappropriate nutritional practices. Advances in genomic technologies have made the concept of individualized nutrition an achievable goal just like the concept of individualized medicine. The fine-tuning of nutritional intervention will require a thorough understanding of nutrient-mediated effects at the molecular level.

Carcinogenesis: Mechanisms and Models

Abstract The three main classes of agents causing cancers are chemicals, radiation, and viruses. Development of cancer is a multistep process; the steps are initiation, promotion, and progression. The International Agency for Research on Cancer has classified carcinogens into five groups: Group 1 (known carcinogen), Group 2A (probable carcinogen), Group 2B (possible carcinogen), Group 3 (not classifiable as a carcinogen), and Group 4 (not carcinogenic). Tests most frequently used to determine the carcinogenic activity of a compound include long-term bioassays and short-term assays. Building of databases of known/suspected carcinogenic compounds has helped in the development of computer programs that can predict the carcinogenic potential of new compounds using quantitative structure-activity relationships. These programs provide additional tools when there is ambiguous data or insufficient data to infer safety.

Chapter 17 – The Biology of Nutrients: Genetic and Molecular Principles*

Abstract The intake of nutrients for growth, repair, and energy is an age-old, intuitive concept of nutrition regarding the role of nutrients in the body. Unlike treating diseases with drug interventions, treating adverse nutritional consequences (e.g., obesity) with nutritional intervention has remained elusive. This is, at least in part, due to the acute nature of the adverse effects of disease as opposed to the chronic nature of the adverse effects of inappropriate nutritional practices. Advances in genomic technologies have made the concept of individualized nutrition an achievable goal just like the concept of individualized medicine. The fine-tuning of nutritional intervention will require a thorough understanding of nutrient-mediated effects at the molecular level.

The Biology of Nutrients: Genetic and Molecular Principles**The opinions expressed in this chapter are the authors’ personal opinions and do not necessarily reflect those of the FDA, DHHS, or the Federal Government.

Abstract The intake of nutrients for growth, repair, and energy is an age-old, intuitive concept of nutrition regarding the role of nutrients in the body. Unlike treating diseases with drug interventions, treating adverse nutritional consequences (e.g., obesity) with nutritional intervention has remained elusive. This is, at least in part, due to the acute nature of the adverse effects of disease as opposed to the chronic nature of the adverse effects of inappropriate nutritional practices. Advances in genomic technologies have made the concept of individualized nutrition an achievable goal just like the concept of individualized medicine. The fine-tuning of nutritional intervention will require a thorough understanding of nutrient-mediated effects at the molecular level.

CHAPTER 22 – Carcinogenesis: mechanisms and models*

Animals have always been exposed to thousands of chemical substances in their daily lives. This exposure may come from the food they eat, the water they drink, the air they breathe, etc. A high level of exposure to many of these chemicals may cause cancer in humans and animals. Cancer is a term that is commonly used to indicate a group of diseases characterized by uncontrolled cell proliferation and usually the spread of these abnormal cells. The three main classes of agents (carcinogens) causing cancers are chemicals, radiation, and viruses. In this chapter, chemical carcinogenesis is emphasized, and viral and radiation carcinogenesis is discussed briefly. Cancer has become an increasingly prominent disease in recent times, but incidence of cancer is documented through writings thousands of years ago. Recent advances in molecular genetics have provided researchers with additional tools to study the mechanisms and the molecular biology of cancer. The knowledge gained from such studies form the foundation of ones understanding of the process of carcinogenesis.