We report here that PON1 levels plateau between 6 to 15 months of age, and that variability in the age at which PON1 levels plateau is quite variable among individuals. In mice and rats, plasma PON1 activity reaches a plateau at 3 weeks of age. In mice that lack endogenous PON1, human transgenes encoding either PON1(Q192) or PON1(R192) under the control of the human PON1 regulatory sequences exhibited a similar time course of expression as that seen in wild-type mice, indicating conservation of the developmental regulatory elements between mouse and human PON1.

These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.

Paraoxonase 1 (PON1) is an HDL associated enzyme that catalyzes a number of different reactions including the hydrolysis of the toxic oxon metabolites of the insecticides diazinon and chlorpyrifos. PON1 has also been implicated in the detoxication of oxidized lipids and the metabolism of a number of drugs, activating some, while inactivating others. There are two common PON1 coding region polymorphisms (L55M and Q192R). The latter determines the catalytic efficiency of hydrolysis of a number of substrates including chlorpyrifos oxon, but not diazoxon.Evidence for the physiological importance of PON1 in modulating exposures to these two insecticides comes from several different studies. Early studies noted that species with high levels of PON1 were much more resistant to certain organophosphorus (OP) insecticides than were species with low levels. Another early study by Main demonstrated that injected rabbit paraoxonase protected rats from paraoxon toxicity. Our research group began the development of a mouse model system for examining the importance of PON1 in the detoxication of OP insecticides. The first sets of experiments demonstrated that injecting purified rabbit PON1 into rats or mice significantly increased resistance to chlorpyrifos and chlorpyrifos oxon, thus demonstrating that high PON1 levels were protective against exposure. They also showed that the protection afforded to chlorpyrifos oxon exposure was significantly better than provided for chlorpyrifos exposure. A survey of reported oxon values in foliar residues indicated that there are oxon residues in most exposures.The consequences of low levels of plasma PON1 were examined in PON1 knockout mice generated by Lusis, Shih and co-workers at UCLA. These mice were found to be highly sensitive to exposures to either diazoxon or chlorpyrifos oxon, but surprisingly not to paraoxon. Examination of the catalytic efficiencies of PON1 for hydrolysis of each of these oxons provided a clear explanation for these observations. While PON1 R192 hydrolyzed paraoxon ninetimes more efficiently than PON1 Q192 (6.27 vs. 0.71), the efficiency was not sufficient to provide protection against a paraoxon exposure. On the other hand, the catalytic efficiencies for hydrolysis of diazoxon by the two PON1-192 alloforms were equivalent and ten-times more efficient (∼77) than for hydrolysis of paraoxon by PON1 R192 . PON1 R192 had significantly greater catalytic efficiency (250) for hydrolyzing chlorpyrifos oxon than did PON1Q192 (150), and both were significantly higher than the efficiency of PON1 R192 for hydrolyzing paraoxon. Injection of the two purified human PON1-192 alloforms into PON1 knockout mice reconstituted the PON1 null mice with either of the human alloforms. These animals were challenged 4 h later with paraoxon, diazoxon, or chlorpyrifos oxon. The 182

This note evaluates the advantages of mediation to resolve custody and visitation disputes when lesbian couples end their relationships. Traditionally, the court system has been reluctant to grant custody to “legal strangers” or third parties. Therefore, mediation has become a more responsive forum to resolve such disputes. This note analyzes several different mediation options available through community‐based resources.