Background-The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results-The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event (Pϭ0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96] Key Words: myocardial infarction Ⅲ lipoproteins Ⅲ coronary disease Ⅲ antioxidants P araoxonase (EC.3.1.8.1, aryldialkylphosphatase) (PON1) has been extensively studied in the field of toxicology because it hydrolyses organophosphate compounds, used as insecticides and nerve gases. 1,2 PON1 is synthesized in the liver and in serum is located on HDL. The serum HDL concentration is inversely correlated with atherosclerosis risk. 3 The mechanism for this continues to be the subject of considerable debate. The initial focus of attention was on the role of HDL in reverse-cholesterol transport. However, recent studies have suggested more diverse mechanisms. HDL protects against oxidative modification of LDL, 4 -6 which is believed to be central to the initiation and progression of atherosclerosis. 7 The antioxidant activity of HDL relates to its enzymes, primarily PON1, but also LCAT, 8 and these can prevent lipid-peroxide accumulation on LDL both in vitro and in vivo. 9 -14 PON1 activity is partly genetically determined. An amino acid substitution at position 192 (Q3 R) gives rise to 2 allozymes, 15,16 the relative activities of which are substrate dependent. Substrates, such as paraoxon and fenitroxon, are hydrolyzed faster by the R alloenzyme, whereas other substrates, such as phenyl acetate, are hydrolyzed at the same rate by both alloenzymes, and yet others, such as diazoxon and the nerve gases soman and sarin, are hydrolyzed more rapidly by the Q alloenzyme. 17 The Q alloenzyme in vitro provides greater protection against the accumulation of lipid peroxides on LDL than the R alloenzyme. 18,19 A second exonic polymorphism of the PON1 gene occurs at amino acid position 55 (L3 M). This polymorphism also affects PON1 activity, although less than that of the 192 polymorphism. 20 There have been many case-control studies to test the hypothesis that the 192R allele of the PON1 gene is associated with coronary heart disease (CHD). 21 A recent metaanalysis of these found that the PON1-192R allele was significantly related to the presence of CHD, but there was evidence of publication bias. 22 Furthermore, genetic casecontrol studies fail to test the hypothesis that serum PON1 activity protects against CHD, because the 192 polymorphism accounts for only a small part of the 40-fold individual variation in serum PON1 act...

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, we investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague-Dawley rats were exposed to repeated social defeat for five days while controls were placed into a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology.

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