Icans for comparison. Q-values are corrected for FDR and the boxed section of the table highlights compounds with Q,0.05. doi:10.1371/journal.pone.0057639.tOverall ��-Sitosterol ��-D-glucoside site changes and mechanismWe show for the first time a significant difference in the metabolic 
signature of atenolol treatment between Caucasians and African Americans. Looking at the global changes Anlotinib price induced by atenolol (Table 3 and Figure 1), there is a strong signature consisting mainly of plasma free fatty acids, presumably involving either a change in the relative rates of synthesis and/or breakdown. Metabolic pathway analysis, described below, indicates that these fatty acids are not related directly by synthetic pathways (for example b-oxidation). Thus, alteration in a single synthetic pathway could not account for the coordinated changes. An effect on basal lipolysis would be the most obvious potential mechanism for the major changes in fatty acids observed here: 
the hydrolysis of triglycerides to free fatty acids and glycerol, followed by further fatty acid breakdown via beta oxidation. Lipolysis is stimulated by hormones, including epinephrine and norepinephrine, and is up-regulated by the b-adrenergic receptors and downregulated by a2-adrenergic receptors. Epinephrine, a non-specific beta-adrenergic agonist, stimulates lipolysis via the b3-adrenoreceptor (ADRB3). Atenolol specifically, and b-blockers generally, have an effect on plasma lipoprotein metabolism by increasing plasma triglyceride levels and decreasing HDL but not affecting LDL [31]. The effect on triglycerides is smaller with atenolol than propanolol, likely due to the relative b1-receptor selectivity of atenolol [31]. Both atenolol and propanolol have been shown to reduce free fatty acid levels [32]. If the reduction in plasma fatty acids were due primarily to general lipolysis, then a corresponding change in both plasma glycerol and glycerol-3-phosphate levels would also be expected, as these are products of triglyceride breakdown. Perhaps the endogenous levels of these compounds are sufficiently large relative to the change in their levels so as to mask the change from observation. A second possible mechanism for the fatty acid changes observed may be the direct effect of atenolol on phospholipase activity (Figure 3). This mechanism is conceptually similar to that of changes in lipolysis, although the upstream signaling interaction would be different. There is circumstantial evidence suggesting that b-blockers inhibit lysosomal phospholipase A and C [33]. Atenolol specifically has been found to inhibit lysosomalphospholipase A1, although with less potency than propanolol [34]. This suggests the possibility of a specific mechanism in which atenolol may bind to and inhibit particular phospholipases in plasma or other related tissues (Figure 3). Atenolol has been shown to bind to bee venom phospholipase A2 and form a stable complex. This mechanism also allows for a potential explanation of racial variance, as phospholipase activity has been shown to vary as a function of both sex and race. Lipoprotein-associated phospholipase A2 (Lp-PLA2), for example, was 15 lower in African American individuals compared with Caucasian subjects [35]. Higher concentrations of Lp-PLA2 are associated withFigure 3. Alternative model of a potential mechanism for atenolol treatment on plasma free fatty acid concentrations. doi:10.1371/journal.pone.0057639.gEthnic Differences in Exposure to Atenololincreased cardiovascular risk, an.Icans for comparison. Q-values are corrected for FDR and the boxed section of the table highlights compounds with Q,0.05. doi:10.1371/journal.pone.0057639.tOverall changes and mechanismWe show for the first time a significant difference in the metabolic signature of atenolol treatment between Caucasians and African Americans. Looking at the global changes induced by atenolol (Table 3 and Figure 1), there is a strong signature consisting mainly of plasma free fatty acids, presumably involving either a change in the relative rates of synthesis and/or breakdown. Metabolic pathway analysis, described below, indicates that these fatty acids are not related directly by synthetic pathways (for example b-oxidation). Thus, alteration in a single synthetic pathway could not account for the coordinated changes. An effect on basal lipolysis would be the most obvious potential mechanism for the major changes in fatty acids observed here: the hydrolysis of triglycerides to free fatty acids and glycerol, followed by further fatty acid breakdown via beta oxidation. Lipolysis is stimulated by hormones, including epinephrine and norepinephrine, and is up-regulated by the b-adrenergic receptors and downregulated by a2-adrenergic receptors. Epinephrine, a non-specific beta-adrenergic agonist, stimulates lipolysis via the b3-adrenoreceptor (ADRB3). Atenolol specifically, and b-blockers generally, have an effect on plasma lipoprotein metabolism by increasing plasma triglyceride levels and decreasing HDL but not affecting LDL [31]. The effect on triglycerides is smaller with atenolol than propanolol, likely due to the relative b1-receptor selectivity of atenolol [31]. Both atenolol and propanolol have been shown to reduce free fatty acid levels [32]. If the reduction in plasma fatty acids were due primarily to general lipolysis, then a corresponding change in both plasma glycerol and glycerol-3-phosphate levels would also be expected, as these are products of triglyceride breakdown. Perhaps the endogenous levels of these compounds are sufficiently large relative to the change in their levels so as to mask the change from observation. A second possible mechanism for the fatty acid changes observed may be the direct effect of atenolol on phospholipase activity (Figure 3). This mechanism is conceptually similar to that of changes in lipolysis, although the upstream signaling interaction would be different. There is circumstantial evidence suggesting that b-blockers inhibit lysosomal phospholipase A and C [33]. Atenolol specifically has been found to inhibit lysosomalphospholipase A1, although with less potency than propanolol [34]. This suggests the possibility of a specific mechanism in which atenolol may bind to and inhibit particular phospholipases in plasma or other related tissues (Figure 3). Atenolol has been shown to bind to bee venom phospholipase A2 and form a stable complex. This mechanism also allows for a potential explanation of racial variance, as phospholipase activity has been shown to vary as a function of both sex and race. Lipoprotein-associated phospholipase A2 (Lp-PLA2), for example, was 15 lower in African American individuals compared with Caucasian subjects [35]. Higher concentrations of Lp-PLA2 are associated withFigure 3. Alternative model of a potential mechanism for atenolol treatment on plasma free fatty acid concentrations. doi:10.1371/journal.pone.0057639.gEthnic Differences in Exposure to Atenololincreased cardiovascular risk, an.
