更多资讯

Techniques such as calorimetry, spectroscopy, and hydrodynamic methods can be used to investigate the binding energetics of drugs bound to macromolecules. In this chapter, the authors describe the use of isothermal titration calorimetry (ITC) to measure the binding energetics of dr ...

A brief summary of the pioneering work of Brodie, Gillette, and coworkers on the discovery and development of the concept of chemically reactive intermediates serves as the backdrop for this chapter on approaches to studying how chemicals modify thiols and other cellular nucleophiles. As ...

Transporters that use ATP are called ATP-binding cassette (ABC) transporters. One family of ABC transporters that plays a major role in the ability of the liver to eliminate various drugs is the multidrug resistance proteins (MRPs). There are nine cloned genes in the MRP (ABCC) subfamily. Gener ...

Besides its important role in folate homeostasis, membrane transport is a critical determinant of the antitumor activities of antifolate therapeutics used in cancer chemotherapy, such as methotrexate (MTX) and an exciting new generation of antifolates typified by Tomudex and Pem ...

Although investigators have often focused on the role of glutathione (GSH) in drug metabolism and protection from reactive oxygen species and toxic electrophiles, membrane transport processes also play a critical role in the overall homeostasis of GSH in the body. Although the liver is the ...

Sulfation is a major reaction in phase II drug and xenobiotic metabolism. It is catalyzed by a family of enzymes, the sulfotransferases (SULTs), and involves the enzymatic transfer of a sulfonate group from a donor molecule (known as 3′-phosphoadenosine 5′-phosphosulfate ) to either an hydro ...

It is widely recognized that the kidneys contain several enzymes capable of catalyzing the metabolism of drugs and toxicants to yield chemically reactive metabolites that can cause nephrotoxicity. Reactive metabolites generated in the kidneys, and metabolites translocated to t ...

This chapter uses cytochrome P450 1A1 (CYP1A1) as a model “xenobiotic inducible” gene and the aryl hydrocarbon receptor (AHR) as a regulator of this gene product to illustrate how studies may be performed to understand the relationships between the regulator protein and its target genes. The m ...

Expression of drug-metabolizing enzymes may be altered in response to development, aging, gender, genetics, nutrition, pregnancy, disease states such as diabetes, long-term alcohol consumption, and inflammation, and by xenobiotics. Although the mechanisms by which xenobioti ...

The zeta class of glutathione S-transferases (GSTZ) is one of the most recently discovered soluble GST classes and has proved to be of considerable interest because of its contribution to the catabolism of phenylalanine and tyrosine and its role in α-halo acid metabolism. GSTZ was originally d ...

This chapter summarizes methods and experimental approaches involved in the study of glucuronidation of several naturally occurring metabolites of the free fatty acids (FFAs), linoleic acid (LA), and arachidonic acid (AA). Data on FA glucuronidation from both human liver micro-som ...

Recent evidence has been provided that five nuclear receptors (NRs), (pregnane X receptor , constitutive androstane receptor , farnesoid X receptor and peroxisome proliferator-activated receptor ) regulate the expression of UGT1A loci. This chapter presents an overview of the most ...

Variation among the human population in the ability to acetylate drugs has been known since the observations on individual variations in isoniazid toxicity in the 1950s. The genetic basis for this was soon appreciated and has come to be known as the N-acetylation polymorphism. This chapter pr ...

Although acetaminophen (also known as paracetamol) is a relatively safe and freely available analgesic, frequent organ toxicity (primarily in the liver) and admissions to emergency rooms occur. The aim of this chapter is to indicate selectively the most promising areas of research into t ...

Antiviral therapies are an important, emerging area of pharmaceutical research, particularly with the advent of the AIDS epidemic and the continued existence of other virally mediated diseases. This chapter focuses on pharmacological approaches to treat these diseases and summ ...

There have been many attempts in the past to determine whether significant levels of Adriamycin-DNA adducts form in cells and contribute to the anticancer activity of this agent. Supraclincal drug levels have been required to study drug-DNA adducts because of the lack of sensitivity assoc ...

Electrospray mass spectrometry can be used to detect ligand-DNA noncovalent complexes formed in solution. This chapter describes how to determine equilibrium association constants of the complexes. Particular attention is devoted to describing how to tune an electrospray mass ...

The design of new DNA-targeted molecules, primarily for use in the therapy of diseases such as cancer, relies on the assessment of both affinity for DNA and selectivity of binding to choosen base pair sequences. Capillary electrophoresis, with a polymer added to the running buffer, is very well sui ...

DNA�RNA hybrid duplexes are functionally important structures in gene expression that are underutilized as potential drug targets. Several tools are described here for the discovery and characterization of small molecules capable of the selective recognition of DNA�RNA hybrid ...

When a drug binds to DNA, its electronic structure is perturbed, and it perturbs the DNA’s electronic structure. The resulting change to the electronic spectroscopy can be used to probe the drug-DNA interaction. This chapter outlines how circular and linear dichroism spectroscopy can be used ...