Lewis Casarett

Bio: Lewis Casarett is an academic researcher. The author has an hindex of 1, co-authored 1 publications receiving 840 citations.

Toxicology: The basic science of poisons

Abstract: THIS is a weighty and heavily documented textbook which should prove of great value to experimental toxicologists. It is arranged in four sections, each section consisting of a number of chapters reviewing the literature on a single aspect of toxicology. There are 35 contributors. The first section of 150 pages is concerned with general principles of toxicology, the absorption, metabolism and excretion of toxins, and the way in which these influence the dose response relationship. This rather detailed treatment is probably not appropriate for medical readers who would be better served by consulting medical textbooks of pharmacology and biochemistry. However, it should be valuable to non-medical toxicologists. In the next two sections occupying 400 pages, the current experimental toxicological field is reviewed in two ways. First by going through the systems of the body (central nervous system, liver, kidney, etc.) and second by going through all the groups of toxins (teratogens, carcinogens, pesticides, metals, etc.). Consequently, there is an almost complete duplication of information in these two sections. This is made worse by a duplication of coverage between say the section on carcinogens which deals with metals and the section on metals which deals with carcinogenesis. This duplication of coverage, coupled with the emphasis on information derived from animal experiments and neglect of clinical information, reduces the value of the book to medical readers.

Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Abstract: Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.

An atlas of genetic influences on human blood metabolites

Abstract: Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism thus far, comprising 7,824 adult individuals from 2 European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity with more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information on gene expression, heritability and overlap with known loci for complex disorders, inborn errors of metabolism and pharmacological targets. We further developed a database and web-based resources for data mining and results visualization. Our findings provide new insights into the role of inherited variation in blood metabolic diversity and identify potential new opportunities for drug development and for understanding disease.

Comparison of primary human hepatocytes and hepatoma cell line HEPG2 with regard to their biotransformation properties

Abstract: Cultures of primary hepatocytes and hepatoma cell line HepG2 are frequently used in in vitro models for human biotransformation studies. In this study, we characterized and compared the capacity of these model systems to indicate the presence of different classes of promutagens. Genotoxic sensitivity, enzyme activity, and gene expression were monitored in response to treatment with food promutagens benzo[a]pyrene, dimethylnitrosamine (DMN), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). DNA damage could be detected reliably with the comet assay in primary human hepatocytes, which were maintained in sandwich culture. All three promutagens caused DNA damage in primary cells, but in HepG2 no genotoxic effects of DMN and PhIP could be detected. We supposed that the lack of specific enzymes accounts for their inability to process these promutagens. Therefore, we quantified the expression of a broad range of genes coding for drug-metabolizing enzymes with real-time reverse transcription-polymerase chain reaction. The genes code for cytochromes p450 and, in addition, for a series of important phase II enzymes. The expression level of these genes in human hepatocytes was similar to those previously reported for human liver samples. On the other hand, expression levels in HepG2 differed significantly from that in human. Activity and expression, especially of phase I enzymes, were demonstrated to be extremely low in HepG2 cells. Up-regulation of specific genes by test substances was similar in both cell types. In conclusion, human hepatocytes are the preferred model for biotransformation in human liver, whereas HepG2 cells may be useful to study regulation of drug-metabolizing enzymes.