2-chlorohexadecanoic acid

Endotoxin treatment of rodents leading to inflammation has been shown to lead to the production of chlorinated lipids. As previously described, Sattler and coworkers showed that endotoxin treatment led to neuroinflammation with concomitant increased levels of both MPO mRNA and 2-chlorohexadecanal in the brain (Ullen et al. 2010). Our studies have also shown that endotoxin leads to chlorinated lipid production in various systems in vivo (Brahmbhatt et al. 2010). In fact, lipopolysaccharide treatment led to elevated 2-chlorohexadecanoic acid levels in the plasma. These studies also delineated the metabolic clearance pathway for 2-chlorohexadecanoic acid, which is mediated by sequential hepatic co-oxidation, P-oxidation from the co-end, and then subsequent excretion of 2-chloroadipic acid in the urine (Figure 4.3). Furthermore, lipopolysaccharide treatment of rats led to not only the elevation of plasma 2-chlorohexadecanoic acid, but also increased excretion of 2-chloroadipic acid in the urine. 

Chlorohexadecanal and 2-chlorohexadecanoic acid are a chemoattractant and chemorepellant, respectively, for neutrophils (Anbukumar et al. 2010 Thukkani et al. 2002). Thus, 2-chlorohexadecanal may be produced as a result of infiltration and activation of neutrophils, and initially participate in the recruitment of additional neutrophils. However, the conversion of 2-chlorohexadecanal into 2-chlorohexadecanoic acid, may have an important role in decelerating further neutrophil recruitment. Also, it should be appreciated that the tandem production of 2-chlorohexadecanal and unsaturated molecular species of lysophosphatidylcholine (and perhaps their chlorohydrins) may enhance neutrophil infiltration by not only chemoattraction, but also stimulating the surface expression of P-selectin (Messner et al. 2008 Thukkani et al. 2003b). 

While significant studies have focused on the biological roles of a-chlorofatty aldehyde, the roles of its metabolites need to be assessed, and the potential roles assigned to a-chlorofatty aldehyde that are actually mediated by its metabolites should be considered. Since both 2-chlorohexadecanal and 2-chlorohexadecanoic acid increase endothelial COX-2 levels, it is possible that 2-chlorohexadecanal does not directly elicit COX-2 expression, but rather its fatty add metabolite may be the mediator of this pathway (Anbukumar et al. 2010 Messner et al. 2008). It should be noted that the role of metabolites of both a-bromofatty aldehyde and a-iodofatty aldehyde remain to be examined. 

---