Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects.

Edited by Lucio G. Costa and Clement E. Furlong Boston, MA: Kluwer Academic, 2002. 216 pp. ISBN: 1-4020-7282-1, $95 cloth.

Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects is a complete and timely review of the biochemistry, genetics, and toxicology of the enzyme paraoxonase. The 10 chapters in the volume provide a comprehensive summary of the current knowledge concerning PON1. The history of the discovery and the biochemical characterization of the enzyme set the stage for the subsequent discussion of the genetic polymorphisms, role in lipid metabolism, atherosclerosis and disease, species variation, and organophosphate toxicity.

The discovery of this genetic polymorphism predated the Human Genome Project and illustrates how pharmacogenetics had to be done in the pregenomic era. The story of PON1 begins with the identification of an enzyme having organophosphates as substrates. Reports of the geographic differences in population frequencies of paraoxonase activity and genetic analysis led to uncovering the genetic polymorphism. At the time, the ramifications of the polymorphism seemed to be limited to populations exposed to a relatively discrete group of xenobiotics. But that was only the beginning, as astute observations led to uncovering a physiologic mechanism through which PON1 protects against oxidative damage of low-density lipoproteins. Subsequently, PON1 has been shown to be a risk factor for coronary artery disease. There are also data implicating PON1 in other diseases and in Gulf War Syndrome, although more research is needed is these areas. This scientific history of PON1 is an excellent example of how genetics, toxicology, biochemistry, and physiology work in concert to understand the basis of human health.

The chapters provide a thorough review of the literature in order to demonstrate the critical functions of PON1 following insecticide exposure and in cardiovascular disease. One important discussion involves the use of either genotype or phenotype in determining individual risk. A convincing argument is made that both pieces of information are essential. PON1 polymorphisms in the coding region have been identified. The PON1 192 variation alters catalytic activity. There is also a significant interindividual variation in levels of the PON1 protein. Thus, the determination of PON1 status that is defined by both gene sequence and enzyme activity is a more realistic appraisal of individual capacity and subsequent risk. This demonstration that genotype alone may not be an accurate predictor of risk clearly has implications for other polymorphisms.

This volume focuses on one gene, yet it will be of interest to scientists from multiple disciplines. There is also no doubt that it is a valuable tool for teaching pharmacogenetics. In this age where putting together genes, functions, and consequences of variation is receiving considerable attention, PON1 provides a road map of the twists and turns that such investigations can and do take. The story of PON1 is still unfolding, and even less is known about PON2 and PON3. The final chapter highlighting future directions is a fitting way to end the volume.

CHARLENE A. MCQUEEN

Charlene A. McQueen is located at the University of Arizona, where she is a member of the Department of Pharmacology and Toxicology, the Southwest Environmental Health Sciences Center, and the Arizona Cancer Center. Her research in pharmaco/toxicogenetics focuses on arylamine N-acetyltransferases.