Neil C. Corley

Microtubule-associated protein

Brain tissue of subjects with Alzheimers disease (AD) differs from normal brain tissue by accumulation of abnormal filamentous elements in neurons to form neurofibrillary tangles (NFTs) and extracellularly to form amyloid in senile plaques. Alzheimer neurofibrillary degeneration involves posttranslational modification of tau proteins by different mechanisms. Phosphorylated sites in paired helical filaments (PHFs)-tau have been identified, most of which reside at regions flanking the microtubule binding domain. Multiple sites for glycation were identified in the tau molecule as well. Many of the glycation sites were distributed within the microtubule binding domain. These modifications alter the function of tau by decreasing its accessibility to tubulin binding, leading to a reduction in microtubule polymerization and stability. These posttranslational modifications also affect the degradation of tau by proteases. Depending on the acidity of the environment in which the tau molecule resides, proteolytic degradation of tau could generate fragments competent for the assembly of filamentous structures. It is found that development of agents capable of preventing or reducing undesirable modification or degradation of tau could be of therapeutic value in treating AD.

Human glutathione-S-transferase

Human glutathione S-transferases (GSTs) are a functionally diverse family of soluble enzymes of detoxification that use reduced glutathione (GSH) in conjugation and reduction reactions. Toxic electrophiles, including a variety of carcinogens, are substrates for the GSTs and after conjugation or reduction they are more easily excreted into bile or urine. Many of the GSTs have been cloned, and the three-dimensional structures of GSTs from several species, including humans, have been determined. These data have provided significant insight into how the GSTs function as enzymes. Many GST substrates are inducers of GST gene expression; nonsubstrate inducers include H2O2 and other reactive oxygen species. The regulatory elements of several human GST genes have been partially characterized, and the regulation of the GSTs in humans appears to be very different from that in rodents. Several polymorphisms of GST expression occur commonly in humans and have been associated with an increased susceptibility to certain cancers, particularly when combined with other genetic and environmental factors such as smoking. The role of GSTs in protecting cells from injury by toxic electrophiles continues to be developed.

Human N-acetyl transferase

Human variability in drug acetylation was discovered nearly four decades ago during the initial clinical trials of isoniazid as an antituberculosis drug (reviewed in Weber 1987). Isoniazid was a remarkably effective therapeutic agent, but, despite its effectiveness, a high proportion (3.5%–17%) of treated patients developed a devastating, progressive nerve toxicity. Pharmacokinetic studies of isoniazid elimination in twins and in families revealed serum concentrations of tuberculostatic forms of the drug distributed into two (or three) genetically determined subgroups. This led to the proposal that persons with low blood levels be classified as “rapid” inactivators and those with high levels as “slow” inactivators of isoniazid (Mitchell and Bell 1957). Later, after the genetic variability (polymorphism) in drug levels was attributed to differences in N-acetyltransferase (NAT)1 activity (Jenne et al. 1961; Jenne 1965; Evans and White 1964), the term “inactivator” was supplanted by “acetylator.” Since then, the two genetically distinct major phenotypes have usually been referred to as rapid and slow acetylators.