This chapter provides a brief overview of the history of studies on human paraoxonases. It honors the memory of the late Dr. Bert La Du (1920-2005), who with his graduate students, postdoctoral fellows and collaborators made many contributions to our knowledge of this family of enzymes and the genes that encode them. Dr. La Du was honored for these contributions at the First International Conference on Paraoxonases (PONs) - "Paraoxonases: Basic and Clinical Directions of Current Research" held in Ann Arbor, Michigan in 2004. Many of the scientists who trained with and/or collaborated with the late Dr. La Du were present at this Second International Conference on Paraoxonases and have contributed to this volume. This chapter begins with a review of some of the early esterase enzymology and the discovery of plasma paraoxonase activity. The pioneering work of Dr. Norman Aldridge who differentiated the A- and B-esterases is described. The studies that defined the polymorphic distribution of PON1 in human populations are discussed along with the many different biochemical assays that were developed to explore this interesting polymorphism. The experiments that led to the purification and cloning of human and rabbit PON1s are described along with the properties of this first enzyme know to retain its signal sequences for use in anchoring it into the HDL particle are discussed. Recent advances by Tawfik and co-workers which include the generation of a PON1 sequence that could be expressed, crystallized and characterized are presented along with the characterization of the many different substrates of this promiscuous enzyme including physiological lactone and xenobiotic lactone substrates. The lactonase activities were characterized by both Tawfik's team and Dr. La Du's research group. The expression and characterization of PON1, PON2 and PON3 by Dr. La Du's research team is also discussed. This effort along with related work by other research groups has greatly expanded our knowledge of the many different activities of the PON family of enzymes. It is probably appropriate to include these proteins in the antioxidant family of proteins. The history of the role of the PONs in lipid metabolism and the association of the genetic variability in the PON family of enzymes is discussed. The important take home lesson from understanding the relationship of genetic variability of PON1 and risk for vascular disease was often stressed by Dr. La Du as well as other leaders in PON1 research is that is both the quantity (plasma PON1 level) as well as the quality of PON1 (position 192 genotype) that need to be considered when evaluating risk of disease. Experiments on the relationship of the genetic variability of PON1 and risk of exposure to organophosphorus compounds are also discussed. The take home message isthe same, in some cases the quality of PON1 (Q192R) is important, but in all cases, the quantity of plasma PON1 is important. This consideration holds for all epidemiological studies that examine the relationship of PON genetic variability and disease.
